CCP-BioSim: Biomolecular simulation at the life sciences interface

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

Biomolecular simulation is a vibrant and growing area, making increasingly significant contributions to structural and systems biology. Physics-based simulations complement experiments in building a molecular level understanding of biology: they can test hypotheses and interpret and analyse experimental data in terms of interactions at the atomic level. A wide variety of simulation techniques have been developed, applicable to a range of different problems in biomolecular science. Simulations have already shown their worth in helping to analyse how enzymes catalyse biochemical reactions, and how proteins adopt their functional structures e.g. within cell membranes. They contribute to the design of drugs and catalysts, and in understanding the molecular basis of disease. Simulations have played a key role in developing the conceptual framework now at the heart of biomolecular science, that is, the understanding that the way that biological molecules move and flex - their dynamics - is central to their function. Developing methods from chemical physics and computational science will open exciting new opportunities in biomolecular science, including in drug design and development, biotechnology and biocatalysis. Much biomolecular simulation demands HPC resources: e.g. large-scale simulations of biological machines such as the ribosome, proton pumps and motors, membrane receptor complexes and even whole viruses. A particular challenge is the integration of simulations across length and timescales: different types of simulation method are required for different types of problems).

We propose to establish a new collaborative computational project in biomolecular simulation at the life sciences interface, CCP-BioSim. CCP-BioSim will be an inclusive wide-ranging project, bringing together chemists, physicists and chemical engineers as well as researchers from all branches of 'molecule-oriented' biochemistry and biology. Our aim will be to involve experimentalists and computational specialists, sharing the belief that the best science can be done when theory and experiment are closely integrated. We will invite all current CCPB members (more than 300) to join CCP-BioSim, and also any other researchers who are interested. Members will be informed of activities via the CCP-BioSim mailing list and the CCP-BioSim website. CCP-BioSim will aim to identify methodological and computational challenges in the field, and to foster develoments to meet these scientific challenges. Involvement of early career academics will also be an important goal: the training workshops we will run will help in establishing research groups. CCP-BioSim will also provide a networking and collaboration framework. The strategy will be to concentrate on activities that promote and facilitate high-impact biomolecular research. We will foster close and innovative interactions between computational and experimental scientists, encouraging integrated multidisciplinary studies. CCP-BioSim will develop and provide training and tools to lower the barrier to non-experts becoming proficient and productive users of biomolecular simulation techniques. We will also work to develop and apply advanced methods. Engagement with experimentalists is crucial to ensure that the methodologies delivered are relevant to biological problems. This is a rapidly developing field: the best science comes from new simulation techniques and state-of-the-art (especially high performance computing (HPC)) hardware and software, requiring methodological development and significant and varied software development effort, in the context of UK and international projects.

Planned Impact

Who will benefit from this research?
As well as biosimulation specialists, a broad cross-section of bioscientists who are concerned, in some way or other, with the nature and behaviour of biomolecules at the atomic level. Eg: X-ray crystallographers, NMR Spectroscopists, Electron microscopists, Single-molecule biophysicists, Mass spectrometrists, Hydrodynamicists, Enzyme Kineticists, Medicinal Chemists, Chemical Biologists, Molecular Microbiologists.
The project will also help identify and develop the needs of the bio-community for high performance computing facilities. It will therefore benefit those bodies concerned with the development of the national and international roadmap for future HPC provision.
In the longer term, there is the potential for the project to impact on the general public through improvements in health and quality of life.

How will they benefit from this research?
The "molecule-oriented" bioscience community will benefit through access to tools, training, and trained simulation specialists that enable novel and more effective multidisciplinary projects where computational methods enhance and extend their core experimental approaches. Such integrated studies have a higher probability of producing high-impact discoveries and developments and so fostering such activities will enhance UK competitiveness in the international research arena. The CCP-BioSim project will provide tools and resources to facilitate this. These tools should give rise to major benefits (e.g. high-impact papers, major international grant awards) over the term of the project, and in future. In the longer term CCP-BioSim will be helping train a new generation of bioscientists who can work confidently and knowledgeably across the theory/experimental divide. What is 'state-of-the-art' today with regard to computational power and methodology, and so might be regarded as somewhat esoteric, will be on the desktop of any bioscientist in 5-10 years time. Impacts on the health and quality of life of the general public are likely to come primarily from the application of the methodologies fostered and disseminated by CCP-BioSim to drug design and discovery. Computational methods are already well-established in Pharma, since they can hasten and cheapen the process of drug discovery and development. The more computationally-intensive methods of biomolecular simulation are gaining ground, as improvements in computational power make accuracy and time-to-solution competitive with 'wet' methods. CCP-BioSim's activities will help improve this by a) helping train new generations of researchers with the necessary skills and b) providing a forum to enhance industrial-academic research links (members of the CCPB management group have established links with many large and smaller pharmaceutical/biotech companies, (AZ, Vernalis, Phaminox, GSK, Evotec, J&J, Pfizer...). The benefits to the public in the longer term come from new and/or cheaper medicinal products, plus the role that better computational methods have in addressing the 3Rs.

What will be done to ensure that they benefit from this research?
CCP-BioSim activities are focussed precisely on ensuring this:
- The programme of workshops, co-organised with leading experimentalists in key disciplines, examining and fostering links across the simulation/experimental interface
- The annual conference focused on exemplifying and encouraging the highest quality interdisciplinary research.
- Training workshops introducing non-specialist bioscientists to high quality simulation methods, and specialists to the latest technological advances.
- Associated on-line training packages, available any time, any place.
- Training workshops and tools developed to aid access to HPC resources for those with a bioscience background.

Tools, software and data from development work will be made freely available, and disseminated via the website. Involvement of a wide community will ensure broad uptake.

Publications

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Acevedo-Rocha C (2018) P450-Catalyzed Regio- and Diastereoselective Steroid Hydroxylation: Efficient Directed Evolution Enabled by Mutability Landscaping in ACS Catalysis

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Ainsley J (2018) Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms. in Advances in protein chemistry and structural biology

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Ainsley J (2018) Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase. in ACS omega

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Ali HS (2019) Entropy of Simulated Liquids Using Multiscale Cell Correlation. in Entropy (Basel, Switzerland)

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Althorpe SC (2016) Non-adiabatic reactions: general discussion. in Faraday discussions

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Amaro RE (2018) Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures. in Nature reviews. Chemistry

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Amaro RE (2020) Biomolecular Simulations in the Time of COVID19, and After. in Computing in science & engineering

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Amaro RE (2020) A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19. in Journal of chemical information and modeling

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Amos STA (2021) Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR. in The journal of physical chemistry. B

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Angulo G (2016) New methods: general discussion. in Faraday discussions

 
Title The Wasteland 
Description I. The Burial of the Dead April is the cruellest month, breeding Lilacs out of the dead land, mixing Memory and desire, stirring Dull roots with spring rain. Winter kept us warm, covering Earth in forgetful snow, feeding A little life with dried tubers. Summer surprised us, coming over the Starnbergersee With a shower of rain; we stopped in the colonnade, And went on in sunlight, into the Hofgarten, And drank coffee, and talked for an hour. Bin gar keine Russin, stamm' aus Litauen, echt deutsch. And when we were children, staying at the arch-duke's, My cousin's, he took me out on a sled, And I was frightened. He said, Marie, Marie, hold on tight. And down we went. In the mountains, there you feel free. I read, much of the night, and go south in the winter. What are the roots that clutch, what branches grow Out of this stony rubbish? Son of man, You cannot say, or guess, for you know only A heap of broken images, where the sun beats, And the dead tree gives no shelter, the cricket no relief, And the dry stone no sound of water. Only There is shadow under this red rock, (Come in under the shadow of this red rock), And I will show you something different from either Your shadow at morning striding behind you Or your shadow at evening rising to meet you; I will show you fear in a handful of dust. Frisch weht der Wind Der Heimat zu Mein Irisch Kind, Wo weilest du? "You gave me hyacinths first a year ago; "They called me the hyacinth girl." -Yet when we came back, late, from the Hyacinth garden, Your arms full, and your hair wet, I could not Speak, and my eyes failed, I was neither Living nor dead, and I knew nothing, Looking into the heart of light, the silence. Oed' und leer das Meer. Madame Sosostris, famous clairvoyante, Had a bad cold, nevertheless Is known to be the wisest woman in Europe, With a wicked pack of cards. Here, said she, Is your card, the drowned Phoenician Sailor, (Those are pearls that were his eyes. Look!) Here is Belladonna, the Lady of the Rocks, The lady of situations. Here is the man with three staves, and here the Wheel, And here is the one-eyed merchant, and this card, Which is blank, is something he carries on his back, Which I am forbidden to see. I do not find The Hanged Man. Fear death by water. I see crowds of people, walking round in a ring. Thank you. If you see dear Mrs. Equitone, Tell her I bring the horoscope myself: One must be so careful these days. Unreal City, Under the brown fog of a winter dawn, A crowd flowed over London Bridge, so many, I had not thought death had undone so many. Sighs, short and infrequent, were exhaled, And each man fixed his eyes before his feet. Flowed up the hill and down King William Street, To where Saint Mary Woolnoth kept the hours With a dead sound on the final stroke of nine. There I saw one I knew, and stopped him, crying: "Stetson! "You who were with me in the ships at Mylae! "That corpse you planted last year in your garden, "Has it begun to sprout? Will it bloom this year? "Or has the sudden frost disturbed its bed? "Oh keep the Dog far hence, that's friend to men, "Or with his nails he'll dig it up again! "You! hypocrite lecteur!-mon semblable,-mon frère!" II. A Game of Chess The Chair she sat in, like a burnished throne, Glowed on the marble, where the glass Held up by standards wrought with fruited vines From which a golden Cupidon peeped out (Another hid his eyes behind his wing) Doubled the flames of sevenbranched candelabra Reflecting light upon the table as The glitter of her jewels rose to meet it, From satin cases poured in rich profusion; In vials of ivory and coloured glass Unstoppered, lurked her strange synthetic perfumes, Unguent, powdered, or liquid-troubled, confused And drowned the sense in odours; stirred by the air That freshened from the window, these ascended In fattening the prolonged candle-flames, Flung their smoke into the laquearia, Stirring the pattern on the coffered ceiling. Huge sea-wood fed with copper Burned green and orange, framed by the coloured stone, In which sad light a carvéd dolphin swam. Above the antique mantel was displayed As though a window gave upon the sylvan scene The change of Philomel, by the barbarous king So rudely forced; yet there the nightingale Filled all the desert with inviolable voice And still she cried, and still the world pursues, "Jug Jug" to dirty ears. And other withered stumps of time Were told upon the walls; staring forms Leaned out, leaning, hushing the room enclosed. Footsteps shuffled on the stair. Under the firelight, under the brush, her hair Spread out in fiery points Glowed into words, then would be savagely still. "My nerves are bad tonight. Yes, bad. Stay with me. "Speak to me. Why do you never speak. Speak. "What are you thinking of? What thinking? What? "I never know what you are thinking. Think." I think we are in rats' alley Where the dead men lost their bones. "What is that noise?" The wind under the door. "What is that noise now? What is the wind doing?" Nothing again nothing. "Do "You know nothing? Do you see nothing? Do you remember "Nothing?" I remember Those are pearls that were his eyes. "Are you alive, or not? Is there nothing in your head?" But O O O O that Shakespeherian Rag- It's so elegant So intelligent "What shall I do now? What shall I do?" "I shall rush out as I am, and walk the street "With my hair down, so. What shall we do tomorrow? "What shall we ever do?" The hot water at ten. And if it rains, a closed car at four. And we shall play a game of chess, Pressing lidless eyes and waiting for a knock upon the door. When Lil's husband got demobbed, I said- I didn't mince my words, I said to her myself, HURRY UP PLEASE ITS TIME Now Albert's coming back, make yourself a bit smart. He'll want to know what you done with that money he gave you To get yourself some teeth. He did, I was there. You have them all out, Lil, and get a nice set, He said, I swear, I can't bear to look at you. And no more can't I, I said, and think of poor Albert, He's been in the army four years, he wants a good time, And if you don't give it him, there's others will, I said. Oh is there, she said. Something o' that, I said. Then I'll know who to thank, she said, and give me a straight look. HURRY UP PLEASE ITS TIME If you don't like it you can get on with it, I said. Others can pick and choose if you can't. But if Albert makes off, it won't be for lack of telling. You ought to be ashamed, I said, to look so antique. (And her only thirty-one.) I can't help it, she said, pulling a long face, It's them pills I took, to bring it off, she said. (She's had five already, and nearly died of young George.) The chemist said it would be all right, but I've never been the same. You are a proper fool, I said. Well, if Albert won't leave you alone, there it is, I said, What you get married for if you don't want children? HURRY UP PLEASE ITS TIME Well, that Sunday Albert was home, they had a hot gammon, And they asked me in to dinner, to get the beauty of it hot- HURRY UP PLEASE ITS TIME HURRY UP PLEASE ITS TIME Goonight Bill. Goonight Lou. Goonight May. Goonight. Ta ta. Goonight. Goonight. Good night, ladies, good night, sweet ladies, good night, good night. III. The Fire Sermon The river's tent is broken: the last fingers of leaf Clutch and sink into the wet bank. The wind Crosses the brown land, unheard. The nymphs are departed. Sweet Thames, run softly, till I end my song. The river bears no empty bottles, sandwich papers, Silk handkerchiefs, cardboard boxes, cigarette ends Or other testimony of summer nights. The nymphs are departed. And their friends, the loitering heirs of city directors; Departed, have left no addresses. By the waters of Leman I sat down and wept . . . Sweet Thames, run softly till I end my song, Sweet Thames, run softly, for I speak not loud or long. But at my back in a cold blast I hear The rattle of the bones, and chuckle spread from ear to ear. A rat crept softly through the vegetation Dragging its slimy belly on the bank While I was fishing in the dull canal On a winter evening round behind the gashouse Musing upon the king my brother's wreck And on the king my father's death before him. White bodies naked on the low damp ground And bones cast in a little low dry garret, Rattled by the rat's foot only, year to year. But at my back from time to time I hear The sound of horns and motors, which shall bring Sweeney to Mrs. Porter in the spring. O the moon shone bright on Mrs. Porter And on her daughter They wash their feet in soda water Et O ces voix d'enfants, chantant dans la coupole! Twit twit twit Jug jug jug jug jug jug So rudely forc'd. Tereu Unreal City Under the brown fog of a winter noon Mr. Eugenides, the Smyrna merchant Unshaven, with a pocket full of currants C.i.f. London: documents at sight, Asked me in demotic French To luncheon at the Cannon Street Hotel Followed by a weekend at the Metropole. At the violet hour, when the eyes and back Turn upward from the desk, when the human engine waits Like a taxi throbbing waiting, I Tiresias, though blind, throbbing between two lives, Old man with wrinkled female breasts, can see At the violet hour, the evening hour that strives Homeward, and brings the sailor home from sea, The typist home at teatime, clears her breakfast, lights Her stove, and lays out food in tins. Out of the window perilously spread Her drying combinations touched by the sun's last rays, On the divan are piled (at night her bed) Stockings, slippers, camisoles, and stays. I Tiresias, old man with wrinkled dugs Perceived the scene, and foretold the rest- I too awaited the expected guest. He, the young man carbuncular, arrives, A small house agent's clerk, with one bold stare, One of the low on whom assurance sits As a silk hat on a Bradford millionaire. The time is now propitious, as he guesses, The meal is ended, she is bored and tired, Endeavours to engage her in caresses Which still are unreproved, if undesired. Flushed and decided, he assaults at once; Exploring hands encounter no defence; His vanity requires no response, And makes a welcome of indifference. (And I Tiresias have foresuffered all Enacted on this same divan or bed; I who have sat by Thebes below the wall And walked among the lowest of the dead.) Bestows one final patronising kiss, And gropes his way, finding the stairs unlit . . . She turns and looks a moment in the glass, Hardly aware of her departed lover; Her brain allows one half-formed thought to pass: "Well now that's done: and I'm glad it's over." When lovely woman stoops to folly and Paces about her room again, alone, She smoothes her hair with automatic hand, And puts a record on the gramophone. "This music crept by me upon the waters" And along the Strand, up Queen Victoria Street. O City city, I can sometimes hear Beside a public bar in Lower Thames Street, The pleasant whining of a mandoline And a clatter and a chatter from within Where fishmen lounge at noon: where the walls Of Magnus Martyr hold Inexplicable splendour of Ionian white and gold. The river sweats Oil and tar The barges drift With the turning tide Red sails Wide To leeward, swing on the heavy spar. The barges wash Drifting logs Down Greenwich reach Past the Isle of Dogs. Weialala leia Wallala leialala Elizabeth and Leicester Beating oars The stern was formed A gilded shell Red and gold The brisk swell Rippled both shores Southwest wind Carried down stream The peal of bells White towers Weialala leia Wallala leialala "Trams and dusty trees. Highbury bore me. Richmond and Kew Undid me. By Richmond I raised my knees Supine on the floor of a narrow canoe." "My feet are at Moorgate, and my heart Under my feet. After the event He wept. He promised a 'new start.' I made no comment. What should I resent?" "On Margate Sands. I can connect Nothing with nothing. The broken fingernails of dirty hands. My people humble people who expect Nothing." la la To Carthage then I came Burning burning burning burning O Lord Thou pluckest me out O Lord Thou pluckest burning IV. Death by Water Phlebas the Phoenician, a fortnight dead, Forgot the cry of gulls, and the deep sea swell And the profit and loss. A current under sea Picked his bones in whispers. As he rose and fell He passed the stages of his age and youth Entering the whirlpool. Gentile or Jew O you who turn the wheel and look to windward, Consider Phlebas, who was once handsome and tall as you. V. What the Thunder Said After the torchlight red on sweaty faces After the frosty silence in the gardens After the agony in stony places The shouting and the crying Prison and palace and reverberation Of thunder of spring over distant mountains He who was living is now dead We who were living are now dying With a little patience Here is no water but only rock Rock and no water and the sandy road The road winding above among the mountains Which are mountains of rock without water If there were water we should stop and drink Amongst the rock one cannot stop or think Sweat is dry and feet are in the sand If there were only water amongst the rock Dead mountain mouth of carious teeth that cannot spit Here one can neither stand nor lie nor sit There is not even silence in the mountains But dry sterile thunder without rain There is not even solitude in the mountains But red sullen faces sneer and snarl From doors of mudcracked houses If there were water And no rock If there were rock And also water And water A spring A pool among the rock If there were the sound of water only Not the cicada And dry grass singing But sound of water over a rock Where the hermit-thrush sings in the pine trees Drip drop drip drop drop drop drop But there is no water Who is the third who walks always beside you? When I count, there are only you and I together But when I look ahead up the white road There is always another one walking beside you Gliding wrapt in a brown mantle, hooded I do not know whether a man or a woman -But who is that on the other side of you? What is that sound high in the air Murmur of maternal lamentation Who are those hooded hordes swarming Over endless plains, stumbling in cracked earth Ringed by the flat horizon only What is the city over the mountains Cracks and reforms and bursts in the violet air Falling towers Jerusalem Athens Alexandria Vienna London Unreal A woman drew her long black hair out tight And fiddled whisper music on those strings And bats with baby faces in the violet light Whistled, and beat their wings And crawled head downward down a blackened wall And upside down in air were towers Tolling reminiscent bells, that kept the hours And voices singing out of empty cisterns and exhausted wells. In this decayed hole among the mountains In the faint moonlight, the grass is singing Over the tumbled graves, about the chapel There is the empty chapel, only the 
Type Of Art Creative Writing 
Impact Inspiration for grant applications and reporting in ResearchFish 
URL https://en.wikipedia.org/wiki/The_Waste_Land
 
Description CCP-BioSim was established in October 2011 with support from EPSRC to strengthen, promote and develop biomolecular simulation at the life sciences interface, an area that is increasingly contributing to biology, biocatalysis and important in drug design. We aim to identify methodological and computational challenges in this growing field, and develop links between academia and industry, and between theorists and experimentalists. CCP-BioSim received the top grade of 'Excellent' at mid-term review, with the Panel commenting "The management of the CCP has been excellent, the value for money has been outstanding to date, and this CCP has a real opportunity to put down a marker for UK science. The Widening Participation funding has also been put to excellent use. CCP-BioSim is an excellent example of a CCP supporting a growing community of researchers." Since that review, we have refreshed our Management Group, and expanded our Advisory Board, building further links with industry (particularly the pharmaceutical industry). The Advisory Board has been expanded and refreshed for this renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). The Management Group (current members listed in Part 1) has met eleven times since October 2011.
CCP-BioSim organizes training workshops and provides a framework for networking and collaboration. We develop and provide training and tools to lower the barrier to non-experts becoming proficient and productive users of biomolecular simulation techniques. We also work to develop and apply advanced methods, and engage with international activities (e.g. NSF, CECAM). We welcome new members across the whole community. We actively engage with structural and chemical biologists and industrial researchers through collaboration, dissemination and application of software, and invitations to conferences and workshops. We foster interactions between computational and experimental scientists, encouraging integrated multidisciplinary studies. We have a particular focus on multiscale modelling (e.g. in current flagship software development). Software tools have been made available via CCP-Forge. We are also developing tools for setting up and analysing biomolecular simulations. Outreach activities include hosting visits from experimental researchers, research visits to industrial partners, web-based training materials and research exemplars and presentations. CCP-BioSim also led a successful bid to EPSRC for a High End Computing Consortium in Biomolecular Simulation (hecbiosim.ac.uk). Working with CCP-BioSim, this Consortium helps bring HEC to a wider community, including non-traditional users and experimental bioscientists, and engage physical and computer scientists in biological applications.
Biomolecular simulations contribute to drug development (e.g. in structure-based drug design and predictions of metabolism), design of biomimetic catalysts, and in understanding the molecular bases of disease and drug resistance. Recent examples include simulations of biosensors and nanopores for DNA sequencing, and analysis of the causes of influenza resistance to Tamiflu. Advances in hardware and software now allow simulations on the microsecond (and even millisecond) timescale, enabling direct links with experiments. Simulations have proved crucial in analysing protein folding and mechanisms of biological catalysis. Developing methods from chemical physics and computational science will open new opportunities for new types and scales of application. A particular challenge is the integration of simulations of different types across length and timescales. We have developed a multiscale modelling approach for modelling drug metabolism by cytochrome P450 enzymes, spanning coarse-grained and atomistic molecular dynamics simulations, and reaction modelling using QM/MM methods. An essential aspect is the sharing of simulation data from different levels: we have developed scripts and procedures for conversion between the three different levels of simulation (available from ccpforge.cse.rl.ac.uk). We have applied this protocol to the most important human P450 in drug metabolism, CYP3A4, constructed and optimized a biologically realistic model of CYP3A4 in situ, simulated the dynamics of this complex, and modelled the oxidation of R-warfarin in the active site. The protocol that we have developed will be applicable to many other membrane-bound enzymes. Publications from the flagship project include: A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes PLoS Comput Biol. 10:e1003714; Trends in predicted chemoselectivity of cytochrome P450 oxidation. J Mol Graph Model. 52 30 (2014); QM/MM modelling of drug-metabolizing enzymes. Curr. Top. Med. Chem. 14, 1339 (2014); Quantum mechanics/molecular mechanics modeling of regioselectivity of drug metabolism in cytochrome P450 2C9. J. Am. Chem. Soc. 135, 8001 (2013). Effects of Dispersion in Density Functional Based Quantum Mechanical/Molecular Mechanical Calculations on Cytochrome P450 Catalyzed Reactions J. Chem. Theory Comput. 8, 4637-4645 (2012). A conformational landscape for alginate secretion across the outer membrane of Pseudomonas aeruginosa. Acta Crystallogr D Biol Crystallogr. 70, 2054 (2014); The role of 2-methyl-2, 4-pentanediol in sodium dodecyl sulfate micelle dissociation unveiled by dynamic light scattering and molecular dynamics simulations. Colloids Surf B Biointerfaces 114, 357 (2014). Dodecyl maltoside protects membrane proteins in vacuo. Biophys J. 105, 648 (2013); Structural model for the protein-translocating element of the twin-arginine transport system. PNAS USA 110 E1092-10101 (2013).
Exploitation Route In CCP-BioSim, we plan for networking, training and conferences, industrial pilot projects and international engagement. We will expand our international and industrial engagement, as recommended by the mid-term review. We will build on our previous widening participation activities, and continue to work with other CCPs in areas of joint interest such as multiscale modelling (e.g. CCP5). We will also engage with the HEC BioSim Consortium to foster HEC applications (see HECBioSim.ac.uk).
1. Training workshops These will include existing workshops (e.g. analysis of biomolecular simulation data; how to set up a protein simulation; QM/MM methods; and protein-ligand docking), and new workshops on a wide variety of techniques (e.g. coarse-grained methods, metadynamics, Markov models, multiscale modelling). These workshops are held at institutions across the whole country, organized by specialists from the Management Group, and others. We have found high demand for these workshops, particularly from PhD students. A particular focus will be to introduce non-specialists, particularly early-stage researchers, to high-quality biomolecular simulation techniques. We will run certain core courses (e.g., how to set up protein MD simulations) annually, and others (e.g. QM/MM methods, docking) at least once every three years. We propose to develop new courses in response to community need (e.g. multiscale modelling, protein-protein docking, metadynamics, Monte Carlo methods, homology modelling; 'Markov Modeling' ER and Frank Noe, Berlin), and will include HEC training for bioscientists. We will maintain our policy of offering these workshops free to UK students and academics. They will also be open to industrial researchers at appropriate low cost; we will encourage industrial participation also through attracting industrial researchers to participate in delivering workshops, providing material and case studies, and using the workshops as a forum for potential employers. The Advisory Board will guide development of workshop material and content to ensure industrial relevance. Participation of software developers, both academic and commercial, will also be encouraged. An important aspect is provision of workshop material via the CCP-BioSim website, which we will extend significantly. Where appropriate, we will continue to work with other organizations (e.g. Molecular Graphics and Modelling Society, EPSRC CDTs, The Biochemical Society, IoP Biological Physics Group and other CCPs (e.g. with CCP5 on QM/MM, free energy, ChemShell and new computational architectures) to deliver joint workshops.
2. Promoting links between experimentalists and computational scientists We propose a series of one-day workshops, aimed at fostering collaborations between experiment and biosimulation, with X-ray crystallography (e.g. with CCP4); NMR (with CCPN); cryo-electron microscopy (with CCP-EM, MW); single molecule biophysics (e.g. with IoP Biological Physics Group, SAH); and synthetic biology (e.g. with BrisSynBio, AJM). These workshops will also build links with experimental and industrial researchers.
3. The annual conference We will continue the successful Frontiers of Biomolecular Simulation conference series (3-day event, typically 100 participants) (previously held in Nottingham, January 2007; Bristol 2008; York 2009; RAC Cirencester 2012; Nottingham 2013; Edinburgh, 2014; Leeds, 2015). This meeting, which is unique in Europe, attracts high quality speakers. The focus of the conference is methodological development and state-of-the-art applications, in particular high accuracy calculations of mechanisms, multi-level methods, and large-scale biomolecular simulations. Involvement of PhD students and early stage researchers will continue to be a focus, as will industrial involvement (previous conferences have attracted sponsorship from companies such as Syngenta, Accelrys, GSK and Clearspeed, and industrial speakers (e.g. AstraZeneca, Evotec, GSK, etc).
4. Website development and outreach We will continue to develop the CCP-BioSim website (ccpbiosim.ac.uk) with increased accessibility and ease of use. The website will include increased emphasis on training material developed for our specialist workshops, and also (with our blog, ccpbiosim.tumblr.com) provide an interactive, collaborative space for user-generated content. This space will be used by the community to post questions, tutorials, simulation input files and conference announcements. The aim will be to provide a forum for interaction between computational experts, experimentalists, and students. This will ensure that simulation best practice is shared rapidly and provide a forum for discussion and collaboration. This will allow for the incubation of new ideas, thereby stimulating new project proposals and new collaborative science. Importantly, this will also aid in dissemination and public engagement: simulation 'movies' provide an intuitive and accessible picture of biomolecuar mechanisms e.g. elucidating antibiotic resistance. We will develop interactive simulation demos. Outreach: we will participate in outreach programmes to involve high school students in research, such as the in2science and the Nuffield Foundation schemes. We will seek to develop innovative approaches for outreach and public understanding, e.g. using interactive demos of biomolecular simulation.
5. International engagement We will increase our international engagement, building on recommendations from mid-term review, and continue to coordinate with development of software workflow tools in other countries (e.g. our Sire/OpenMM development, etc.). We will contribute to issues of data standardization by seeking views from the community, defining requirements and challenges, and forming a point of contact for the UK biomolecular simulation community, coordinating with international activities. CAL is involved in the pyPCAZIP (for PCA analysis of MD simulations), a collaboration between the US-UK ExTASY project and the University of Barcelona; this was demoed at a CCP-BioSim training workshop in Bristol (Sept. 2014) and will be released in Oct. 2014; we will organize training workshops involving international participants. JWE and CAL are partners in two large EPSRC-NSF proposals to develop advanced software to facilitate the deployment of sophisticated biomolecular simulation methods in the context of advanced polarizable force fields and the exploitation of collective variables. CCP-BioSim will provide training in the software outputs from these projects. In addition, coordinated by JWE and CAL, CCP-BioSim representatives are attending the 'Conceptualization of an Institute for Biomolecular Simulations' workshops (https://sites.google.com/site/s2i2biomolecular/home) to formulate a proposal to NSF for such an Institute. In Europe, CCPBioSIm representatives participate in many CECAM workshops and in the development of CECAM strategy for computational science (e.g. SK and AJM participated in the CECAM workshop 'A Scientific Roadmap for Simulation and Modelling for 2020', Lugano Oct. 2013, and contributed to the resulting strategy document for Dominic Tildesley, CECAM Director. We will collaborate with international partners in organizing workshops (e.g. software development and training workshops at CECAM nodes, and workshops with the German Biophysical Society, CSCS, FEBS, EMBO).
6. Industrial collaboration We will organize industry 'sandpits' to identify application areas and methods as targets for development and collaboration: in these meetings, challenges and problems from industry will be informally presented along with emerging methods; this will allow 'brain-storming' to help develop of new collaborations. We will also seek proposals for industrial pilot projects across the whole community; applications will be sought from the whole UK community. These will be awarded competitively, with impact and value for money judged by the Management Group. The aim will be to support research visits to industrial sites, to host research visits from industrial visitors, or other industry collaborations.
7. Joint meetings with CCP5 on multiscale modelling methods We will continue our successful joint conference with CCP5 on multiscale methods (first in January 2014). We will also organize two-day training workshops in areas of joint interest with CCP5 (e.g. multiscale simulation, free energy methods), every other year . We will also seek to participate in activities with other CCPs, e.g. forthcoming joint conference with CCPN (2016)

Evidence is emerging that vitamin D - and possibly vitamins K and A - might help combat COVID-19. A new study from the University of Bristol published in the journal of the German Chemical Society Angewandte Chemie has shown how they - and other antiviral drugs - might work. The research indicates that these dietary supplements and compounds could bind to the viral spike protein and so might reduce SARS-CoV-2 infectivity. In contrast, cholesterol may increase infectivity, which could explain why having high cholesterol is considered a risk factor for serious disease.

Recently, Bristol researchers showed that linoleic acid binds to a specific site in the viral spike protein, and that by doing so, it locks the spike into a closed, less infective form. Now, a research team has used computational methods to search for other compounds that might have the same effect, as potential treatments. They hope to prevent human cells becoming infected by preventing the viral spike protein from opening enough to interact with a human protein (ACE2). New anti-viral drugs can take years to design, develop and test, so the researchers looked through a library of approved drugs and vitamins to identify those which might bind to this recently discovered 'druggable pocket' inside the SARS-CoV-2 spike protein.

The team first studied the effects of linoleic acid on the spike, using computational simulations to show that it stabilizes the closed form. Further simulations showed that dexamethasone - which is an effective treatment for COVID-19 - might also bind to this site and help reduce viral infectivity in addition to its effects on the human immune system.

The team then conducted simulations to see which other compounds bind to the fatty acid site. This identified some drugs that have been found by experiments to be active against the virus, suggesting that this may be one mechanism by which they prevent viral replication such as, by locking the spike structure in the same way as linoleic acid.

The findings suggested several drug candidates among available pharmaceuticals and dietary components, including some that have been found to slow SARS-CoV-2 reproduction in the laboratory. These have the potential to bind to the SARS-CoV-2 spike protein and may help to prevent cell entry.

The simulations also predicted that the fat-soluble vitamins D, K and A bind to the spike in the same way making the spike less able to infect cells.

Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry, who modelled the spike, explained: "Our findings help explain how some vitamins may play a more direct role in combatting COVID than their conventional support of the human immune system.

"Obesity is a major risk factor for severe COVID. Vitamin D is fat soluble and tends to accumulate in fatty tissue. This can lower the amount of vitamin D available to obese individuals. Countries in which some of these vitamin deficiencies are more common have also suffered badly during the course of the pandemic. Our research suggests that some essential vitamins and fatty acids including linoleic acid may contribute to impeding the spike/ACE2 interaction. Deficiency in any one of them may make it easier for the virus to infect."

Pre-existing high cholesterol levels have been associated with increased risk for severe COVID-19. Reports that the SARS-CoV-2 spike protein binds cholesterol led the team to investigate whether it could bind at the fatty acid binding site. Their simulations indicate that it could bind, but that it may have a destabilising effect on the spike's locked conformation, and favour the open, more infective conformation.

Dr Shoemark continued: "We know that the use of cholesterol lowering statins reduces the risk of developing severe COVID and shortens recovery time in less severe cases. Whether cholesterol de-stabilises the "benign", closed conformation or not, our results suggest that by directly interacting with the spike, the virus could sequester cholesterol to achieve the local concentrations required to facilitate cell entry and this may also account for the observed loss of circulating cholesterol post infection."

Professor Adrian Mulholland, of Bristol's School of Chemistry, added: "Our simulations show how some molecules binding at the linoleic acid site affect the spike's dynamics and lock it closed. They also show that drugs and vitamins active against the virus may work in the same way. Targeting this site may be a route to new anti-viral drugs. A next step would be to look at effects of dietary supplements and test viral replication in cells."

Alison Derbenwick Miller, Vice President, Oracle for Research, said: "It's incredibly exciting that researchers are gaining new insights into how SARS-CoV-2 interacts with human cells, which ultimately will lead to new ways to fight COVID-19. We are delighted that Oracle's high-performance cloud infrastructure is helping to advance this kind of world-changing research. Growing a globally-connected community of cloud-powered researchers is exactly what Oracle for Research is designed to do."

The team included experts from Bristol UNCOVER Group, including Bristol's Schools of Chemistry, Biochemistry, Cellular and Molecular Medicine, and Max Planck Bristol Centre for Minimal Biology, and BrisSynBio, using Bristol's high performance computers and the UK supercomputer, ARCHER, as well as Oracle cloud computing. The study was supported by grants from the EPSRC and the BBSRC.

Paper

'Molecular simulations suggest vitamins, retinoids and steroids as ligands binding the free fatty acid pocket of SARS-CoV-2 spike protein' by Deborah Karen Shoemark, Charlotte K. Colenso, Christine Toelzer, Kapil Gupta, Richard B. Sessions, Andrew D. Davidson, Imre Berger, Christiane Schaffitzel, James Spencer and Adrian J. Mulholland in Angewandte Chemie International Edition: doi.org/10.1002/anie.20201563
Sectors Chemicals,Creative Economy,Digital/Communication/Information Technologies (including Software),Education,Healthcare,Pharmaceuticals and Medical Biotechnology
URL http://www.ccpbiosim.ac.uk
 
Description AMR Global Development Award 2017
Amount £88,000 (GBP)
Funding ID MR/R014922/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2017 
End 03/2018
 
Description BBSRC Tools and Techniques: Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation
Amount £146,027 (GBP)
Funding ID BB/L018756/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2014 
End 01/2016
 
Description BBSRC sLoLa: Innovative Routes to Monoterpene Hydrocarbons and Their High Value Derivatives
Amount £3,038,984 (GBP)
Funding ID BB/M000354/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2019
 
Description Biocatalysis and Biotransformation: A 5th Theme for the National Catalysis Hub
Amount £3,053,639 (GBP)
Funding ID EP/M013219/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 12/2019
 
Description BristolBridge has contributed to the University of Bristol being the UK's largest recipient of RCUK AMR cross-council funding awards both in number (7) and value (£5.268M). 6 related AMR grants awarded with BristolBridge PIs/Co-Is include MRC-led AMR.
Amount £5,268,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description CCPBioSim: Biomolecular Simulation at the Life Science Interface
Amount £345,687 (FKP)
Funding ID EP/T026308/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 11/2020 
End 10/2025
 
Description Carbapenem Antibiotic Resistance in Enterobacteriaceae: Understanding Interactions of KPC Carbapenemases with Substrates and Inhibitors
Amount £668,396 (GBP)
Funding ID MR/T016035/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2020 
End 01/2023
 
Description Confidence in Concept 'Developing a mobile device for rapid antimicrobial resistance detection in primary care'
Amount £74,685 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2017 
End 05/2018
 
Description EPSRC
Amount £188,950 (GBP)
Funding ID E/EP/G007705/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2013 
End 03/2014
 
Description Synthetic Biology Research Centre. BrisSynBio: Bristol Centre for Synthetic Biology
Amount £13,528,180 (GBP)
Funding ID BB/L01386X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2014 
End 07/2019
 
Title Bristol University uses Oracle Cloud Infrastructure to speed up smoking cessation drug discovery 
Description Scientists from the University of Bristol used Oracle Cloud Infrastructure to speed up research into how nicotine causes addiction by binding to specific receptors in the brain. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2019 
Provided To Others? Yes  
Impact Scientists at the University of Bristol have published research showing how nicotine affects receptors in the brain as part of an effort to design drugs that will help smokers to quit. They have done so using Oracle Cloud Infrastructure donated by the supplier and in collaboration with Achieve Life Sciences, a Seattle-based pharmaceutical company focused on the commercialisation of Cytisinicline, a plant-based alkaloid with a high binding affinity to the nicotinic acetylcholine receptor in the human brain. According to the US National Institute on Drug Abuse, the majority of smokers would like to stop smoking, and each year around half try to quit permanently. Yet, only about 6% of smokers are able to quit in any given year. Smoking is the second most common cause of death worldwide. The paper that issued from the Bristol research, A general mechanism for signal propagation in the nicotinic acetylcholine receptor family, was published in the Journal of the American Chemical Society in December 2019. Two of the authors are from Oracle's Cloud Development Centre in Bristol, Phil Bates and Gerardo Viedma Nunez. Adrian Mulholland from the University of Bristol's Centre for Computational Chemistry was co-lead author on the paper, along with Richard Sessions, senior research fellow at the School of Biochemistry at Bristol. Mulholland told Computer Weekly: "Our work shows how nicotine exerts its effects on nicotinic acetylcholine receptors. Understanding this should help us design better smoking cessation aids." The study, led by led University of Bristol scientists but involving academics from other institutions, used Oracle's cloud infrastructure. The researchers used new computational simulation methods to conduct 450 assessments of the biochemistry associated with the binding of nicotine to a subtype of nicotinic acetylcholine receptors, a mechanism believed to be responsible for the highly addictive nature of the drug. "Each simulation takes eight hours to run on a single cloud node", said Mulholland. "If we had used our own high-performance computing facility, it would have taken 90 days to do what we did in five. "We are lucky at Bristol to have pretty good HPC resources, but what the Oracle Cloud enabled us to do was to run a new class of simulation - 'non-equilibrium' simulations, of which there are hundreds that have to be done in parallel. The Oracle Cloud enabled us to run them in a matter of weeks, whereas it would otherwise have taken us a year. "To understand why nicotine is so addictive, and to develop molecules to help people quit smoking, we need to understand how nicotine affects the nervous system. By harnessing the power of cloud computing, we can quickly observe how nicotine exerts its effects at the molecular level. This information can inform future drug development of new treatments for companies like Achieve." According to a press statement from Achieve Life Sciences, Oracle and Bristol, the university and the pharmaceutical firm have teamed up to "formulate molecules and potential treatments to combat addiction and neurological disorders based on smoking cessation compound in development, cytisinicline". Cytisinicline is, according to the statement, a "plant-based alkaloid with a high binding affinity to the nicotinic acetylcholine receptor. It is believed to aid in smoking cessation by interacting with nicotine receptors in the brain by reducing the severity of nicotine withdrawal symptoms and by reducing the reward and satisfaction associated with smoking." The drug has been approved in Central and Eastern Europe for more than two decades, and has been used by "more than 20 million people", according to the press statement. The paper is one output of research originally funded by the EPSRC in 2016, with £724,000. Mulholland said the beauty of being able to use cloud computing for this sort of scientific research lies in its capacity to enable collaboration. "I'm a great believer in different sorts of scientists working together to get the best results. And that's not about computation in its own right, but as part of a product development programme," he said. "It's helping to inform what sort of molecules people might make to test as potential medicines. Being able to do the computational simulations fast enough so that scientists can design and adapt their experiments quickly should accelerate drug development. We couldn't have done this two years ago." The work brought together computational chemists, biochemists and research software engineers, working together to deploy the simulations of nicotine receptors. The computer simulations methodology used in this particular area of neuroscience could also, said Mulholland, be applied to the study of schizophrenia and Alzheimer's. 
URL https://www.computerweekly.com/news/252476773/Bristol-University-uses-Oracle-Cloud-Infrastructure-to...
 
Title A Multiscale Workflow for Modelling Ligand Complexes of Zinc Metalloproteins 
Description Representative MD trajectories, topologies and input files for the protein:ligand complexes presented in the paper Yang et al. J Chem. Inf. Model. 2021. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Zinc metalloproteins are ubiquitous, with protein zinc centers of structural and functional importance, involved in interactions with ligands and substrates and often of pharmacological interest. Biomolecular simulations are increasingly prominent in investigations of protein structure, dynamics, ligand interactions, and catalysis, but zinc poses a particular challenge, in part because of its versatile, flexible coordination. A computational workflow generating reliable models of ligand complexes of biological zinc centers would find broad application. Here, we evaluate the ability of alternative treatments, using (nonbonded) molecular mechanics (MM) and quantum mechanics/molecular mechanics (QM/MM) at semiempirical (DFTB3) and density functional theory (DFT) levels of theory, to describe the zinc centers of ligand complexes of six metalloenzyme systems differing in coordination geometries, zinc stoichiometries (mono- and dinuclear), and the nature of interacting groups (specifically the presence of zinc-sulfur interactions). MM molecular dynamics (MD) simulations can overfavor octahedral geometries, introducing additional water molecules to the zinc coordination shell, but this can be rectified by subsequent semiempirical (DFTB3) QM/MM MD simulations. B3LYP/MM geometry optimization further improved the accuracy of the description of coordination distances, with the overall effectiveness of the approach depending upon factors, including the presence of zinc-sulfur interactions that are less well described by semiempirical methods. We describe a workflow comprising QM/MM MD using DFTB3 followed by QM/MM geometry optimization using DFT (e.g., B3LYP) that well describes our set of zinc metalloenzyme complexes and is likely to be suitable for creating accurate models of zinc protein complexes when structural information is more limited. 
URL https://data.bris.ac.uk/data/dataset/10p78zgsappbz226bzrdagabq9/
 
Title Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-beta-lactamase in the Imine Form 
Description MD trajectories, topologies, parameters and input files for the data presented in the paper Twidale et al. J Chem. Inf. Model. 2021. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Widespread bacterial resistance to carbapenem antibiotics is an increasing global health concern. Resistance has emerged due to carbapenem-hydrolyzing enzymes, including metallo-ß-lactamases (MßLs), but despite their prevalence and clinical importance, MßL mechanisms are still not fully understood. Carbapenem hydrolysis by MßLs can yield alternative product tautomers with the potential to access different binding modes. Here, we show that a combined approach employing crystallography and quantum mechanics/molecular mechanics (QM/MM) simulations allow tautomer assignment in MßL:hydrolyzed antibiotic complexes. Molecular simulations also examine (meta)stable species of alternative protonation and tautomeric states, providing mechanistic insights into ß-lactam hydrolysis. We report the crystal structure of the hydrolyzed carbapenem ertapenem bound to the L1 MßL from Stenotrophomonas maltophilia and model alternative tautomeric and protonation states of both hydrolyzed ertapenem and faropenem (a related penem antibiotic), which display different binding modes with L1. We show how the structures of both complexed ß-lactams are best described as the (2S)-imine tautomer with the carboxylate formed after ß-lactam ring cleavage deprotonated. Simulations show that enamine tautomer complexes are significantly less stable (e.g., showing partial loss of interactions with the L1 binuclear zinc center) and not consistent with experimental data. Strong interactions of Tyr32 and one zinc ion (Zn1) with ertapenem prevent a C6 group rotation, explaining the different binding modes of the two ß-lactams. Our findings establish the relative stability of different hydrolyzed (carba)penem forms in the L1 active site and identify interactions important to stable complex formation, information that should assist inhibitor design for this important antibiotic resistance determinant. 
URL https://data.bris.ac.uk/data/dataset/13pu85dfaobij2rumzql5buyy2/
 
Title Evolution of dynamical networks enhances catalysis in a designer enzyme 
Description Data related to: "Evolution of dynamical networks enhances catalysis in a designer enzyme". H. Adrian Bunzel, J. L. Ross Anderson, Donald Hilvert, Vickery L. Arcus, Marc W. van der Kamp, Adrian J. Mulholland. Nature Chemistry 2021. MD Trajectories of a designed and evolved Kemp eliminase (1A53-2 and 1A53-2.5) in complex with a ground state (GS) or transition state (TS, TS2) model. The ligands are called GS1, TS1, and TS3 in the raw data. Cluster analysis of each trajectory, discriminating between an open (0) or closed (1) state for each frame. Pymol Sessions to reproduce Figures 1-3 of the paper. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Activation heat capacity is emerging as a crucial factor in enzyme thermoadaptation, as shown by the non-Arrhenius behaviour of many natural enzymes. However, its physical origin and relationship to the evolution of catalytic activity remain uncertain. Here we show that directed evolution of a computationally designed Kemp eliminase reshapes protein dynamics, which gives rise to an activation heat capacity absent in the original design. These changes buttress transition-state stabilization. Extensive molecular dynamics simulations show that evolution results in the closure of solvent-exposed loops and a better packing of the active site. Remarkably, this gives rise to a correlated dynamical network that involves the transition state and large parts of the protein. This network tightens the transition-state ensemble, which induces a negative activation heat capacity and non-linearity in the activity-temperature dependence. Our results have implications for understanding enzyme evolution and suggest that selectively targeting the conformational dynamics of the transition-state ensemble by design and evolution will expedite the creation of novel enzymes. 
URL https://data.bris.ac.uk/data/dataset/l6hm9j11yil92bh9rvh27i7ge/
 
Title Simulation of Functional Motions in Enzymes 
Description Data related to: "Structure and function in homodimeric enzymes: simulations of cooperative and independent functional motions". Wells SA, Van der Kamp MW, Mulholland AJ. PLOS ONE, 2015. Results from two different simulation methods, normal-mode biased geometric simulations of flexible motion and conventional molecular dynamics, as applied to two different homodimeric enzymes, the DcpS scavanger decapping enzyme and citrate synthase. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Large-scale conformational change is a common feature in the catalytic cycles of enzymes. Many enzymes function as homodimers with active sites that contain elements from both chains. Symmetric and anti-symmetric cooperative motions in homodimers can potentially lead to correlated active site opening and/or closure, likely to be important for ligand binding and release. Here, we examine such motions in two different domain-swapped homodimeric enzymes: the DcpS scavenger decapping enzyme and citrate synthase. We use and compare two types of all-atom simulations: conventional molecular dynamics simulations to identify physically meaningful conformational ensembles, and rapid geometric simulations of flexible motion, biased along normal mode directions, to identify relevant motions encoded in the protein structure. The results indicate that the opening/closure motions are intrinsic features of both unliganded enzymes. In DcpS, conformational change is dominated by an anti-symmetric cooperative motion, causing one active site to close as the other opens; however a symmetric motion is also significant. In CS, we identify that both symmetric (suggested by crystallography) and asymmetric motions are features of the protein structure, and as a result the behaviour in solution is largely non-cooperative. The agreement between two modelling approaches using very different levels of theory indicates that the behaviours are indeed intrinsic to the protein structures. Geometric simulations correctly identify and explore large amplitudes of motion, while molecular dynamics simulations indicate the ranges of motion that are energetically feasible. Together, the simulation approaches are able to reveal unexpected functionally relevant motions, and highlight differences between enzymes. 
URL http://data.bris.ac.uk/data/dataset/1klro7qjw27xi19qrcs1bb2nt6/
 
Description Modelling of enzyme catalysed reaction mechanisms relevant to pharmaceutical development 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Confidential
Collaborator Contribution Confidential
Impact Confidential
Start Year 2011
 
Title Acquire job scheduler 
Description Demo release of the Acquire job scheduler. The prototype version of the software developed to ease submission and management of jobs to distributed HPC clusters. 
Type Of Technology Grid Application 
Year Produced 2012 
Impact Demo release of the Acquire job scheduler. The prototype version of the software developed to ease submission and management of jobs to distributed HPC clusters. 
URL http://ssi-amrmmhd.epcc.ed.ac.uk/conspire/The_HPC_Cloud.html
 
Title Acquire job scheduler 
Description Production release of the Acquire job scheduler. The production version of the software developed to ease submission and management of jobs to distributed HPC clusters. 
Type Of Technology Grid Application 
Year Produced 2013 
Impact Used as part of CCP5 training workshops in Manchester in 2013 and 2014. 
URL http://ssi-amrmmhd.epcc.ed.ac.uk/conspire/The_HPC_Cloud.html
 
Title BioSimSpace 
Description BioSimSpace is an interoperable Python framework for biomolecular simulation. It is the Flagship Software Development Project of CCP-BioSim. With it you can: -Write robust and portable biomolecular workflow components that work on different hardware, with different software packages, and that can be run in different ways, e.g. command-line, Jupyter. -Interact with running molecular simulation processes in real-time. BioSimSpace is a new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. See: https://biosimspace.org 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact BioSimSpace has been used in several CCP-BioSim training workshops, and is now being applied in collaboration with industrialists and experimentalists. 
URL http://www.ccpbiosim.ac.uk
 
Title CCP-BioSim software for biomolecular simulation 
Description BioSimSpace A new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. This project is currently in an early phase of development, more information can be found here. FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. Other Software: ProtoMS - a complete protein Monte Carlo free energy simulation package. Sire - a complete python/C++ molecular simulation framework, particularly focussed around Monte Carlo, QM/MM and free energy methods. PCAZIP - a toolkit for compression and analysis of molecular dynamics trajectories. COCO - a tool to enrich an ensemble of structures, obtained e.g. from NMR. Handy Routines for Ptraj/Cpptraj - additional analysis methods for ptraj and cpptraj. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact BioSimSpace A new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. This project is currently in an early phase of development, more information can be found here. FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. Other Software: ProtoMS - a complete protein Monte Carlo free energy simulation package. Sire - a complete python/C++ molecular simulation framework, particularly focussed around Monte Carlo, QM/MM and free energy methods. PCAZIP - a toolkit for compression and analysis of molecular dynamics trajectories. COCO - a tool to enrich an ensemble of structures, obtained e.g. from NMR. Handy Routines for Ptraj/Cpptraj - additional analysis methods for ptraj and cpptraj. 
URL http://www.ccpbiosim.ac.uk
 
Title FESetup 
Description FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. 
Type Of Technology Software 
Year Produced 2017 
Impact FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. 
 
Title Longbow v1.5 
Description Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact Longbow has now been downloaded 1,523 times from the HECBioSim website and tens of thousands of times from the pypi directory (July 2017). It has a wide reaching user-base across the world, some of those users being at 26 UK institutions actively downloading new versions as they are released. This version was a major new release which focused on addressing a number of architectural problems, this required major refactoring of the code base. This version fixed a number of community reported bugs and added user requested new functionality. Support for the latest python 3 version was added and the API restructured to simplify uptake in other projects. 
URL https://github.com/HECBioSim/Longbow/releases/tag/v1.5.0
 
Title Sire 2007.1 
Description 2007.1 (first official) release of the Sire molecular simulation framework. This included new methods developed to calculate QM/MM free energies. 
Type Of Technology Software 
Year Produced 2007 
Open Source License? Yes  
Impact Sire is used in several pharmaceutical companies. This version of the code was used to run the simulations in "An efficient method for the calculation of quantum mechanics/molecular mechanics free energies" Christopher J. Woods, Frederick R. Manby and Adrian J. Mulholland J. Chem. Phys. 128 014109 (2008) doi:10.1063/1.2805379 The combination of quantum mechanics (QM) with molecular mechanics (MM) offers a route to improved accuracy in the study of biological systems, and there is now significant research effort being spent to develop QM/MM methods that can be applied to the calculation of relative free energies. Currently, the computational expense of the QM part of the calculation means that there is no single method that achieves both efficiency and rigor; either the QM/MM free energy method is rigorous and computationally expensive, or the method introduces efficiency-led assumptions that can lead to errors in the result, or a lack of generality of application. In this paper we demonstrate a combined approach to form a single, efficient, and, in principle, exact QM/MM free energy method. We demonstrate the application of this method by using it to explore the difference in hydration of water and methane. We demonstrate that it is possible to calculate highly converged QM/MM relative free energies at the MP2/aug-cc-pVDZ/OPLS level within just two days of computation, using commodity processors, and show how the method allows consistent, high-quality sampling of complex solvent configurational change, both when perturbing hydrophilic water into hydrophobic methane, and also when moving from a MM Hamiltonian to a QM/MM Hamiltonian. The results demonstrate the validity and power of this methodology, and raise important questions regarding the compatibility of MM and QM/MM forcefields, and offer a potential route to improved compatibility. 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2009.1 
Description 2009.1 release of the Sire molecular simulation framework. Main enhancement was making the code portable to a wide range of architectures, e.g. including PowerPC/AIX (so that the code could run efficiently on HPCx) and enhancing the functionality of the QM/MM free energy code. 
Type Of Technology Software 
Year Produced 2009 
Open Source License? Yes  
Impact Sire is used in several pharmaceutical companies for applications in drug design and development. This version of the code was used to run the simulations in "Compatibility of Quantum Chemical Methods and Empirical (MM) Water Models in Quantum Mechanics / Molecular Mechanics Liquid Water Simulations", J. Phys. Chem. Lett., doi:10.1021/jz900096p and "Combined Quantum Mechanics Molecular Mechanics (QM MM) Simulations for Protein Ligand Complexes: Free Energies of Binding of Water Molecules in Influenza Neuraminidase", J. Phys. Chem. B, 2014, Accepted 10.1021/jp506413j 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2010.1 
Description 2010.1 release of Sire molecular simulation framework. Main enhancement was the development and inclusion of code to perform waterswap absolute binding free energy calculations. This was the first release of software capable of performing these kinds of calculation. 
Type Of Technology Software 
Year Produced 2010 
Open Source License? Yes  
Impact This version of the code was used to run the simulations in "A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies", Woods, CJ, Malaisree, M, Hannongbua, S & Mulholland, AJ (2011) Journal of Chemical Physics, vol 134, no. 5, 054114 DOI:10.1063/1.3519057, the first application of the WaterSwap method. The accurate prediction of absolute protein-ligand binding free energies is one of the grand challenge problems of computational science. Binding free energy measures the strength of binding between a ligand and a protein, and an algorithm that would allow its accurate prediction would be a powerful tool for rational drug design. Here we present the development of a new method that allows for the absolute binding free energy of a protein-ligand complex to be calculated from first principles, using a single simulation. Our method involves the use of a novel reaction coordinate that swaps a ligand bound to a protein with an equivalent volume of bulk water. This water-swap reaction coordinate is built using an identity constraint, which identifies a cluster of water molecules from bulk water that occupies the same volume as the ligand in the protein active site. A dual topology algorithm is then used to swap the ligand from the active site with the identified water cluster from bulk water. The free energy is then calculated using replica exchange thermodynamic integration. This returns the free energy change of simultaneously transferring the ligand to bulk water, as an equivalent volume of bulk water is transferred back to the protein active site. This, directly, is the absolute binding free energy. It should be noted that while this reaction coordinate models the binding process directly, an accurate force field and sufficient sampling are still required to allow for the binding free energy to be predicted correctly. In this paper we present the details and development of this method, and demonstrate how the potential of mean force along the water-swap coordinate can be improved by calibrating the soft-core Coulomb and Lennard-Jones parameters used for the dual topology calculation. The optimal parameters were applied to calculations of protein-ligand binding free energies of a neuraminidase inhibitor (oseltamivir), with these results compared to experiment. These results demonstrate that the water-swap coordinate provides a viable and potentially powerful new route for the prediction of protein-ligand binding free energies. 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2012.1 
Description 2012.1 release of Sire molecular simulation framework. Main enhancement was the creation of code to simplify the running of waterswap absolute binding free energy calculations. This included new algorithms for automatically generating z-matrices of molecules, automatically loading the molecular structure and parameters from Amber format topology/coordinate files, and the development and inclusion of new algorithms for speeding up the calculation (reflection sphere, grid-based electrostatics etc.) 
Type Of Technology Software 
Year Produced 2012 
Open Source License? Yes  
Impact This version of the code was used to run some of the simulations in "Computational Assay of H7N9 Influenza Neuraminidase Reveals R292K Mutation Reduces Drug Binding Affinity" Scientific Reports, doi:10.1038/srep03561 The emergence of a novel H7N9 avian influenza that infects humans is a serious cause for concern. Of the genome sequences of H7N9 neuraminidase available, one contains a substitution of arginine to lysine at position 292, suggesting a potential for reduced drug binding efficacy. We have performed molecular dynamics simulations of oseltamivir, zanamivir and peramivir bound to H7N9, H7N9-R292K, and a structurally related H11N9 neuraminidase. They show that H7N9 neuraminidase is structurally homologous to H11N9, binding the drugs in identical modes. The simulations reveal that the R292K mutation disrupts drug binding in H7N9 in a comparable manner to that observed experimentally for H11N9-R292K. Absolute binding free energy calculations with the WaterSwap method confirm a reduction in binding affinity. This indicates that the efficacy of antiviral drugs against H7N9-R292K will be reduced. Simulations can assist in predicting disruption of binding caused by mutations in neuraminidase, thereby providing a computational 'assay.' 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2013.1 
Description 2013.1 release of Sire molecular simulation framework. Main enhancement was the creation of a new packaging framework that allowed Sire to be more easily packaged and distributed in source and binary form. This simplified the release management of Sire, and also made it easier for others to download and use the software. In addition, this release marked the first official release of the "waterswap" executable for absolute protein-ligand binding free energy calculations. 
Type Of Technology Software 
Year Produced 2013 
Open Source License? Yes  
Impact This version of the code was downloaded and used by industry (Okada Okimasa, Mitsubishi Tanabe Pharma Co., Japan), and was also the subject of presentation at the DrugDesign2013 conference in Oxford. 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2013.2 
Description 2013.2 release of Sire molecular simulation framework. The main enhancement was the addition of new code that could correctly decompose absolute protein-ligand binding free energies to per-residue and per-water-molecule components. 
Type Of Technology Software 
Year Produced 2013 
Open Source License? Yes  
Impact Sire is used in several pharmaceutical companies for applications in drug design and development. This version of the code was used to perform the simulations that were part of the article "Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water" Christopher J. Woods, Maturos Malaisree, Julien Michel, Ben Long, Simon McIntosh-Smith and Adrian J. Mulholland Faraday Discussions, 2014,169, 477-499 DOI: 10.1039/C3FD00125C 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2014.1 
Description Sire molecular simulation framework. The main enhancement was the development of new code to optimise the waterswap algorithm, e.g. to provide new methods of choosing the water molecules that would be swapped. In addition, new code for monitoring and recording the location of water molecules is included, together with a new "waterview" program that plots water occupation in protein binding sites. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact Sire is used in several pharmaceutical companies for projects in drug design and development. 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2014.2 
Description 2014.2 release of the Sire molecular simulation framework. Main enhancements were the addition of code to calculate molecular surface areas and volumes, and code that could correctly align molecules. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact Sire is used in several pharmaceutical companies for drug design and development projects. This version of the code was used for the EMBO Biomolecular Simulation workshop in Paris in July 2014. http://events.embo.org/14-simulation/ 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2014.3 
Description 2014.3 release of Sire. Main improvement was the inclusion of the quantomm and ligandswap packages for relative binding free energy of QM/MM free energy simulations 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact Used in several pharmaceutical companies for applications in drug design and development 
URL http://www.siremol.org/Sire/Home.html
 
Title Sire 2014.4 
Description 2014.4 release of Sire. Molecular simulation framework. Main enhancement was the inclusion of new code that accelerated key routines. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact Sire is now in use in a number of pharmaceutical companies for applications in drug design and development 
URL http://www.siremol.org/Sire/Home.html
 
Description Atomistic Simulation of Biocatalysts for Non-Experts 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact On February 23rd, a tutorial workshop was held in Manchester, sponsored by the UK catalysis Hub and CCPBiosim and aimed at non-experts to learn about atomistic simulation of biocatalysts. The day included general introduction, the Enlighten simulation protocols & tools, and a "simulation clinic". 25 participants from around the UK (including from industry), with very positive feedback - all having a better idea about atomistic simulation and how to apply it in their research.
Year(s) Of Engagement Activity 2017
URL https://www.eventbrite.com/e/atomistic-simulation-of-biocatalysts-for-non-experts-tickets-3150736136...
 
Description CCPBioSim Training Week 2019 - QM/MM enzyme reaction modelling 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact During the CCPBioSim training week in 2019, I led a training workshop to introduce non-specialists to the use of combined quantum mechanics/molecular mechanics (QM/MM) methods for modelling enzyme-catalysed reaction mechanisms. The open-source course material for this is available online. ~25 people attended, and it was evaluated very positively. Excellent discussion afterwards with several attendees.
Year(s) Of Engagement Activity 2019
URL http://www.ccpbiosim.ac.uk/events/workshop-course-material/eventdetail/120/-/ccpbiosim-training-week...
 
Description CCPBioSim training week 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact From June 7th to 10th, four one-day tutorial workshops were held, covering a range of different biomolecular simulation techniques and hosting several instructors. Relevant research presentations concluded each day. Between 25 and 45 participants attended each day, from all around the UK (and one international). Attendance was free, sponsored by CCPBioSim. Feedback was overwelmingly positive, with many planning to use the techniques taught in their research.
Year(s) Of Engagement Activity 2016
URL http://www.ccpbiosim.ac.uk/events/workshop-course-material