Inquire: Software for real-time analysis of binding
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Recent breakthroughs in hardware and software development allow computer simulations of biological molecules to reach timescales during which interesting biochemical events, such as protein folding, and drug binding and unbinding occur. This allows simulation to be used as a "computational microscope" to zoom in and watch the interactions of biomolecules such as proteins. For example, we have been using molecular dynamics simulations to watch the binding and unbinding of the flu drug Tamiflu(R) to its target protein, called neuraminidase. Using simulation, we can watch Tamiflu(R) unbinding from mutated forms of neuraminidase which we know come from mutants of flu that are drug-resistant, and for which Tamiflu(R) is no-longer an effective treatment. This is allowing us to build a computational assay, which lets us predict which mutations are likely to lead to drug resistance. However, while we can use our computational microscope to watch the drug unbind, merely watching something happen does not give us understanding of why it happens. To enable medicinal drug designers to develop new, mutation-resistant drugs, we need to be able to use computer simulation to gain understanding of the exact chemical details of the molecular interactions between the drug and the protein, and to quantify how those interactions change upon mutation. We have developed new, prototype software that is capable of this task. It is able to quantify the strength of attraction between a drug and a protein, and to quantify the attraction in terms of specific molecular interactions between the drug and individual parts of the protein, and individual water molecules around the drug binding site. We propose to develop and optimise our software, and to also build an intuitive, easy-to-use graphical interface, that will allow drug designers to easily perform this analysis in near-real time on a molecular dynamics trajectory. This will allow drug designers, molecular simulators, and anyone interested in molecular association, to gain an immediate, intuitive understanding of the molecular-scale driving forces to binding. This will aid medicinal researchers in the development of new drugs, and will aid researchers in their quest to understand how mutations in viruses and bacteria can lead to a loss of efficacy of existing drugs.
Technical Summary
Recent breakthroughs in hardware and software development allow condensed-phase molecular dynamics simulations of biomolecular systems to access biochemically relevant timescales (microseconds to milliseconds). Using molecular dynamics, it is now possible to simulate biochemically important events, such as protein folding and drug binding and unbinding. While the ability to perform such dynamics simulations is a leap forward for the field of computational biochemistry, the ability to watch something happening does not provide enough information about why it happens, or the mechanism behind that action. Watching a drug unbind during a dynamics trajectory can suggest that a particular protein mutant is drug resistant, but provides little detail as to how this resistance has been conferred. How has the binding affinity of the drug been reduced? How has the mutation changed the structure of water in the active site to displace the drug? Medicinal chemists need detailed answers to these questions at the molecular scale to enable them to design new features into the drugs to encourage binding and to overcome resistance. Binding free energy calculations provide exactly this type of information.
The aim of this project is to develop software that is capable of near real-time analysis of protein-drug binding. The software will calculate binding free energies, globally, locally (with respect to time) and also decomposed to per-residue and per-active-site water molecule components. The result will be animations and visualisations of protein-drug binding that reveal the molecular detail behind specific interactions between the drug, active-site residues and water molecules. This will guide drug designers by revealing the mechanisms by which a drug achieves a strong binding affinity, and revealing why emerging mutations in protein targets lead to drug resistance.
The aim of this project is to develop software that is capable of near real-time analysis of protein-drug binding. The software will calculate binding free energies, globally, locally (with respect to time) and also decomposed to per-residue and per-active-site water molecule components. The result will be animations and visualisations of protein-drug binding that reveal the molecular detail behind specific interactions between the drug, active-site residues and water molecules. This will guide drug designers by revealing the mechanisms by which a drug achieves a strong binding affinity, and revealing why emerging mutations in protein targets lead to drug resistance.
Planned Impact
The successful completion of this project will lead to new, easy-to-use and intuitive software that will allow molecular designers to easily analyse the large volumes of data produced by molecular dynamics simulations, so that they can inquire about the mechanisms underlying molecular association and protein-drug binding. By making this software freely available, we will provide molecular designers in the pharmaceutical industry with the new ability to rationalise binding between proteins and drugs in terms of rigorously-calculated free energy contributions from individual drug-residue and drug-water interactions. To realise this impact, half of this project will be spent creating a graphical interface that will make such analysis easy to perform, and intuitive to understand. Additionally, by optimising the software so that the calculations can be performed in near-real time, it will provide industrial molecular designers with the ability to design new small molecule drugs in-silico, in 3D in the binding site, with the ability to watch in near-real time as user-guided modifications to the drug affect its local binding free energy, decomposed to interactions with neighbouring protein residues and water molecules. This new capability will raise awareness of the key role played by water molecules in molecular association, and by visualising such interactions, the software will allow molecular designers to create new small molecule drugs that will optimise such drug-water interactions. This, we believe, will have a significant impact on the field of molecular design, providing new routes for the creation of new medicinal drugs, with the obvious societal and economic benefits that this would imply. In addition, this tool will also allow for the rationalisation of the appearance of drug resistance. Our proposed software will allow the industrial molecular designer to see exactly how the protein mutations lead to a drop in drug efficacy, thereby allowing the designer to construct a computational screen, and to have the mechanistic insight to suggest modifications to the drug that would overcome resistance. This would allow owners of patents of now less-effective drugs to re-examine the causes for the loss of efficacy, and in the best case, create subtle derivatives of those drugs that overcome resistance and lead to a resurgence of that drugs saleability. The ability to revisit and update old drugs clearly has the potential for significant positive societal and economic benefits.
Finally, this software will be applicable outside of the field of medicinal drug design, and could be used to rationalise any form of small molecule molecular association, e.g. to rationalise free energy flow in binding of receptors to signalling proteins, or the specific interactions of small molecules passing through channels or interaction with nanoparticles. This provides new and exciting capabilities for molecular designers across a wide range of biomedical and bioengineering disciplines, providing those designers with new, chemical-level quantitative insight coupled to a near-real time graphical design interface. This will support the process of molecular design across this wide range of disciplines enabling it to become significantly quicker, easier and more successful. Molecular design, and particular molecular design targeted at molecular association with biomolecules, provides perhaps one of the most exciting and dynamic endeavours for 21st century science, with significant potential to have wide-ranging and disruptive impact on the industries and societies of tomorrow. By creating intuitive, molecular-level graphical analysis software, we plan to make the process of molecular design significantly easier, which we hope, will help realise the grand potential of this field more quickly.
Finally, this software will be applicable outside of the field of medicinal drug design, and could be used to rationalise any form of small molecule molecular association, e.g. to rationalise free energy flow in binding of receptors to signalling proteins, or the specific interactions of small molecules passing through channels or interaction with nanoparticles. This provides new and exciting capabilities for molecular designers across a wide range of biomedical and bioengineering disciplines, providing those designers with new, chemical-level quantitative insight coupled to a near-real time graphical design interface. This will support the process of molecular design across this wide range of disciplines enabling it to become significantly quicker, easier and more successful. Molecular design, and particular molecular design targeted at molecular association with biomolecules, provides perhaps one of the most exciting and dynamic endeavours for 21st century science, with significant potential to have wide-ranging and disruptive impact on the industries and societies of tomorrow. By creating intuitive, molecular-level graphical analysis software, we plan to make the process of molecular design significantly easier, which we hope, will help realise the grand potential of this field more quickly.
Publications
Ainsley J
(2018)
Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.
in Advances in protein chemistry and structural biology
Ainsley J
(2018)
Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.
in ACS omega
Ali HS
(2019)
Entropy of Simulated Liquids Using Multiscale Cell Correlation.
in Entropy (Basel, Switzerland)
Althorpe SC
(2016)
Non-adiabatic reactions: general discussion.
in Faraday discussions
Amaro RE
(2018)
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.
in Nature reviews. Chemistry
Amaro RE
(2020)
Biomolecular Simulations in the Time of COVID19, and After.
in Computing in science & engineering
Amaro RE
(2020)
A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19.
in Journal of chemical information and modeling
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
Angulo G
(2016)
New methods: general discussion.
in Faraday discussions
Ansell TB
(2021)
Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.
in Journal of chemical theory and computation
| 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 wind's home. |
| Type Of Art | Creative Writing |
| Impact | Inspiration for grant applications and reporting in ResearchFish |
| URL | https://en.wikipedia.org/wiki/The_Waste_Land |
| Description | Recent advances in computational hardware, software and algorithms enable simulations of protein-ligand complexes to achieve timescales during which complete ligand binding and unbinding pathways can be observed. While observation of such events can promote understanding of binding and unbinding pathways, it does not alone provide information about the molecular drivers for protein-ligand association, nor guidance on how a ligand could be optimised to better bind to the protein. We have developed the waterswap (C. J. Woods et al., J. Chem. Phys., 2011, 134, 054114) absolute binding free energy method that calculates binding affinities by exchanging the ligand with an equivalent volume of water. A significant advantage of this method is that the binding free energy is calculated using a single reaction coordinate from a single simulation. This has enabled the development of new visualisations of binding affinities based on free energy decompositions to per-residue and per-water molecule components. These provide a clear picture of which protein-ligand interactions are strong, and which active site water molecules are stabilised or destabilised upon binding. Optimisation of the algorithms underlying the decomposition enables near-real-time visualisation, allowing these calculations to be used either to provide interactive feedback to a ligand designer, or to provide run-time analysis of protein-ligand molecular dynamics simulations. Recent breakthroughs in hardware and software development allow computer simulations of biological molecules to reach timescales during which interesting biochemical events, such as protein folding, and drug binding and unbinding occur. This allows simulation to be used as a "computational microscope" to zoom in and watch the interactions of biomolecules such as proteins. For example, we have been using molecular dynamics simulations to watch the binding and unbinding of the flu drug Tamiflu(R) to its target protein, called neuraminidase. Using simulation, we can watch Tamiflu(R) unbinding from mutated forms of neuraminidase which we know come from mutants of flu that are drug-resistant, and for which Tamiflu(R) is no-longer an effective treatment. This is allowing us to build a computational assay, which lets us predict which mutations are likely to lead to drug resistance. However, while we can use our computational microscope to watch the drug unbind, merely watching something happen does not give us understanding of why it happens. To enable medicinal drug designers to develop new, mutation-resistant drugs, we need to be able to use computer simulation to gain understanding of the exact chemical details of the molecular interactions between the drug and the protein, and to quantify how those interactions change upon mutation. We have developed new, prototype software that is capable of this task. It is able to quantify the strength of attraction between a drug and a protein, and to quantify the attraction in terms of specific molecular interactions between the drug and individual parts of the protein, and individual water molecules around the drug binding site. We propose to develop and optimise our software, and to also build an intuitive, easy-to-use graphical interface, that will allow drug designers to easily perform this analysis in near-real time on a molecular dynamics trajectory. This will allow drug designers, molecular simulators, and anyone interested in molecular association, to gain an immediate, intuitive understanding of the molecular-scale driving forces to binding. This will aid medicinal researchers in the development of new drugs, and will aid researchers in their quest to understand how mutations in viruses and bacteria can lead to a loss of efficacy of existing drugs. Technical Summary Recent breakthroughs in hardware and software development allow condensed-phase molecular dynamics simulations of biomolecular systems to access biochemically relevant timescales (microseconds to milliseconds). Using molecular dynamics, it is now possible to simulate biochemically important events, such as protein folding and drug binding and unbinding. While the ability to perform such dynamics simulations is a leap forward for the field of computational biochemistry, the ability to watch something happening does not provide enough information about why it happens, or the mechanism behind that action. Watching a drug unbind during a dynamics trajectory can suggest that a particular protein mutant is drug resistant, but provides little detail as to how this resistance has been conferred. How has the binding affinity of the drug been reduced? How has the mutation changed the structure of water in the active site to displace the drug? Medicinal chemists need detailed answers to these questions at the molecular scale to enable them to design new features into the drugs to encourage binding and to overcome resistance. Binding free energy calculations provide exactly this type of information. The aim of this project is to develop software that is capable of near real-time analysis of protein-drug binding. The software will calculate binding free energies, globally, locally (with respect to time) and also decomposed to per-residue and per-active-site water molecule components. The result will be animations and visualisations of protein-drug binding that reveal the molecular detail behind specific interactions between the drug, active-site residues and water molecules. This will guide drug designers by revealing the mechanisms by which a drug achieves a strong binding affinity, and revealing why emerging mutations in protein targets lead to drug resistance. Planned Impact The successful completion of this project will lead to new, easy-to-use and intuitive software that will allow molecular designers to easily analyse the large volumes of data produced by molecular dynamics simulations, so that they can inquire about the mechanisms underlying molecular association and protein-drug binding. By making this software freely available, we will provide molecular designers in the pharmaceutical industry with the new ability to rationalise binding between proteins and drugs in terms of rigorously-calculated free energy contributions from individual drug-residue and drug-water interactions. To realise this impact, half of this project will be spent creating a graphical interface that will make such analysis easy to perform, and intuitive to understand. Additionally, by optimising the software so that the calculations can be performed in near-real time, it will provide industrial molecular designers with the ability to design new small molecule drugs in-silico, in 3D in the binding site, with the ability to watch in near-real time as user-guided modifications to the drug affect its local binding free energy, decomposed to interactions with neighbouring protein residues and water molecules. This new capability will raise awareness of the key role played by water molecules in molecular association, and by visualising such interactions, the software will allow molecular designers to create new small molecule drugs that will optimise such drug-water interactions. This, we believe, will have a significant impact on the field of molecular design, providing new routes for the creation of new medicinal drugs, with the obvious societal and economic benefits that this would imply. In addition, this tool will also allow for the rationalisation of the appearance of drug resistance. Our proposed software will allow the industrial molecular designer to see exactly how the protein mutations lead to a drop in drug efficacy, thereby allowing the designer to construct a computational screen, and to have the mechanistic insight to suggest modifications to the drug that would overcome resistance. This would allow owners of patents of now less-effective drugs to re-examine the causes for the loss of efficacy, and in the best case, create subtle derivatives of those drugs that overcome resistance and lead to a resurgence of that drugs saleability. The ability to revisit and update old drugs clearly has the potential for significant positive societal and economic benefits. Finally, this software will be applicable outside of the field of medicinal drug design, and could be used to rationalise any form of small molecule molecular association, e.g. to rationalise free energy flow in binding of receptors to signalling proteins, or the specific interactions of small molecules passing through channels or interaction with nanoparticles. This provides new and exciting capabilities for molecular designers across a wide range of biomedical and bioengineering disciplines, providing those designers with new, chemical-level quantitative insight coupled to a near-real time graphical design interface. This will support the process of molecular design across this wide range of disciplines enabling it to become significantly quicker, easier and more successful. Molecular design, and particular molecular design targeted at molecular association with biomolecules, provides perhaps one of the most exciting and dynamic endeavours for 21st century science, with significant potential to have wide-ranging and disruptive impact on the industries and societies of tomorrow. By creating intuitive, molecular-level graphical analysis software, we plan to make the process of molecular design significantly easier, which we hope, will help realise the grand potential of this field more quickly. |
| Exploitation Route | Recent breakthroughs in hardware and software development allow computer simulations of biological molecules to reach timescales during which interesting biochemical events, such as protein folding, and drug binding and unbinding occur. This allows simulation to be used as a "computational microscope" to zoom in and watch the interactions of biomolecules such as proteins. For example, we have been using molecular dynamics simulations to watch the binding and unbinding of the flu drug Tamiflu(R) to its target protein, called neuraminidase. Using simulation, we can watch Tamiflu(R) unbinding from mutated forms of neuraminidase which we know come from mutants of flu that are drug-resistant, and for which Tamiflu(R) is no-longer an effective treatment. This is allowing us to build a computational assay, which lets us predict which mutations are likely to lead to drug resistance. However, while we can use our computational microscope to watch the drug unbind, merely watching something happen does not give us understanding of why it happens. To enable medicinal drug designers to develop new, mutation-resistant drugs, we need to be able to use computer simulation to gain understanding of the exact chemical details of the molecular interactions between the drug and the protein, and to quantify how those interactions change upon mutation. We have developed new, prototype software that is capable of this task. It is able to quantify the strength of attraction between a drug and a protein, and to quantify the attraction in terms of specific molecular interactions between the drug and individual parts of the protein, and individual water molecules around the drug binding site. We propose to develop and optimise our software, and to also build an intuitive, easy-to-use graphical interface, that will allow drug designers to easily perform this analysis in near-real time on a molecular dynamics trajectory. This will allow drug designers, molecular simulators, and anyone interested in molecular association, to gain an immediate, intuitive understanding of the molecular-scale driving forces to binding. This will aid medicinal researchers in the development of new drugs, and will aid researchers in their quest to understand how mutations in viruses and bacteria can lead to a loss of efficacy of existing drugs. Technical Summary Recent breakthroughs in hardware and software development allow condensed-phase molecular dynamics simulations of biomolecular systems to access biochemically relevant timescales (microseconds to milliseconds). Using molecular dynamics, it is now possible to simulate biochemically important events, such as protein folding and drug binding and unbinding. While the ability to perform such dynamics simulations is a leap forward for the field of computational biochemistry, the ability to watch something happening does not provide enough information about why it happens, or the mechanism behind that action. Watching a drug unbind during a dynamics trajectory can suggest that a particular protein mutant is drug resistant, but provides little detail as to how this resistance has been conferred. How has the binding affinity of the drug been reduced? How has the mutation changed the structure of water in the active site to displace the drug? Medicinal chemists need detailed answers to these questions at the molecular scale to enable them to design new features into the drugs to encourage binding and to overcome resistance. Binding free energy calculations provide exactly this type of information. The aim of this project is to develop software that is capable of near real-time analysis of protein-drug binding. The software will calculate binding free energies, globally, locally (with respect to time) and also decomposed to per-residue and per-active-site water molecule components. The result will be animations and visualisations of protein-drug binding that reveal the molecular detail behind specific interactions between the drug, active-site residues and water molecules. This will guide drug designers by revealing the mechanisms by which a drug achieves a strong binding affinity, and revealing why emerging mutations in protein targets lead to drug resistance. Planned Impact The successful completion of this project will lead to new, easy-to-use and intuitive software that will allow molecular designers to easily analyse the large volumes of data produced by molecular dynamics simulations, so that they can inquire about the mechanisms underlying molecular association and protein-drug binding. By making this software freely available, we will provide molecular designers in the pharmaceutical industry with the new ability to rationalise binding between proteins and drugs in terms of rigorously-calculated free energy contributions from individual drug-residue and drug-water interactions. To realise this impact, half of this project will be spent creating a graphical interface that will make such analysis easy to perform, and intuitive to understand. Additionally, by optimising the software so that the calculations can be performed in near-real time, it will provide industrial molecular designers with the ability to design new small molecule drugs in-silico, in 3D in the binding site, with the ability to watch in near-real time as user-guided modifications to the drug affect its local binding free energy, decomposed to interactions with neighbouring protein residues and water molecules. This new capability will raise awareness of the key role played by water molecules in molecular association, and by visualising such interactions, the software will allow molecular designers to create new small molecule drugs that will optimise such drug-water interactions. This, we believe, will have a significant impact on the field of molecular design, providing new routes for the creation of new medicinal drugs, with the obvious societal and economic benefits that this would imply. In addition, this tool will also allow for the rationalisation of the appearance of drug resistance. Our proposed software will allow the industrial molecular designer to see exactly how the protein mutations lead to a drop in drug efficacy, thereby allowing the designer to construct a computational screen, and to have the mechanistic insight to suggest modifications to the drug that would overcome resistance. This would allow owners of patents of now less-effective drugs to re-examine the causes for the loss of efficacy, and in the best case, create subtle derivatives of those drugs that overcome resistance and lead to a resurgence of that drugs saleability. The ability to revisit and update old drugs clearly has the potential for significant positive societal and economic benefits. Finally, this software will be applicable outside of the field of medicinal drug design, and could be used to rationalise any form of small molecule molecular association, e.g. to rationalise free energy flow in binding of receptors to signalling proteins, or the specific interactions of small molecules passing through channels or interaction with nanoparticles. This provides new and exciting capabilities for molecular designers across a wide range of biomedical and bioengineering disciplines, providing those designers with new, chemical-level quantitative insight coupled to a near-real time graphical design interface. This will support the process of molecular design across this wide range of disciplines enabling it to become significantly quicker, easier and more successful. Molecular design, and particular molecular design targeted at molecular association with biomolecules, provides perhaps one of the most exciting and dynamic endeavours for 21st century science, with significant potential to have wide-ranging and disruptive impact on the industries and societies of tomorrow. By creating intuitive, molecular-level graphical analysis software, we plan to make the process of molecular design significantly easier, which we hope, will help realise the grand potential of this field more quickly. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |
| URL | https://sites.google.com/site/mulhollandresearchgroup/ |
| Description | The software has been used by industrial partners in the UK and abroad. Recent breakthroughs in hardware and software development allow computer simulations of biological molecules to reach timescales during which interesting biochemical events, such as protein folding, and drug binding and unbinding occur. This allows simulation to be used as a "computational microscope" to zoom in and watch the interactions of biomolecules such as proteins. For example, we have been using molecular dynamics simulations to watch the binding and unbinding of the flu drug Tamiflu(R) to its target protein, called neuraminidase. Using simulation, we can watch Tamiflu(R) unbinding from mutated forms of neuraminidase which we know come from mutants of flu that are drug-resistant, and for which Tamiflu(R) is no-longer an effective treatment. This is allowing us to build a computational assay, which lets us predict which mutations are likely to lead to drug resistance. However, while we can use our computational microscope to watch the drug unbind, merely watching something happen does not give us understanding of why it happens. To enable medicinal drug designers to develop new, mutation-resistant drugs, we need to be able to use computer simulation to gain understanding of the exact chemical details of the molecular interactions between the drug and the protein, and to quantify how those interactions change upon mutation. We have developed new, prototype software that is capable of this task. It is able to quantify the strength of attraction between a drug and a protein, and to quantify the attraction in terms of specific molecular interactions between the drug and individual parts of the protein, and individual water molecules around the drug binding site. We propose to develop and optimise our software, and to also build an intuitive, easy-to-use graphical interface, that will allow drug designers to easily perform this analysis in near-real time on a molecular dynamics trajectory. This will allow drug designers, molecular simulators, and anyone interested in molecular association, to gain an immediate, intuitive understanding of the molecular-scale driving forces to binding. This will aid medicinal researchers in the development of new drugs, and will aid researchers in their quest to understand how mutations in viruses and bacteria can lead to a loss of efficacy of existing drugs. Technical Summary Recent breakthroughs in hardware and software development allow condensed-phase molecular dynamics simulations of biomolecular systems to access biochemically relevant timescales (microseconds to milliseconds). Using molecular dynamics, it is now possible to simulate biochemically important events, such as protein folding and drug binding and unbinding. While the ability to perform such dynamics simulations is a leap forward for the field of computational biochemistry, the ability to watch something happening does not provide enough information about why it happens, or the mechanism behind that action. Watching a drug unbind during a dynamics trajectory can suggest that a particular protein mutant is drug resistant, but provides little detail as to how this resistance has been conferred. How has the binding affinity of the drug been reduced? How has the mutation changed the structure of water in the active site to displace the drug? Medicinal chemists need detailed answers to these questions at the molecular scale to enable them to design new features into the drugs to encourage binding and to overcome resistance. Binding free energy calculations provide exactly this type of information. The aim of this project is to develop software that is capable of near real-time analysis of protein-drug binding. The software will calculate binding free energies, globally, locally (with respect to time) and also decomposed to per-residue and per-active-site water molecule components. The result will be animations and visualisations of protein-drug binding that reveal the molecular detail behind specific interactions between the drug, active-site residues and water molecules. This will guide drug designers by revealing the mechanisms by which a drug achieves a strong binding affinity, and revealing why emerging mutations in protein targets lead to drug resistance. Planned Impact The successful completion of this project will lead to new, easy-to-use and intuitive software that will allow molecular designers to easily analyse the large volumes of data produced by molecular dynamics simulations, so that they can inquire about the mechanisms underlying molecular association and protein-drug binding. By making this software freely available, we will provide molecular designers in the pharmaceutical industry with the new ability to rationalise binding between proteins and drugs in terms of rigorously-calculated free energy contributions from individual drug-residue and drug-water interactions. To realise this impact, half of this project will be spent creating a graphical interface that will make such analysis easy to perform, and intuitive to understand. Additionally, by optimising the software so that the calculations can be performed in near-real time, it will provide industrial molecular designers with the ability to design new small molecule drugs in-silico, in 3D in the binding site, with the ability to watch in near-real time as user-guided modifications to the drug affect its local binding free energy, decomposed to interactions with neighbouring protein residues and water molecules. This new capability will raise awareness of the key role played by water molecules in molecular association, and by visualising such interactions, the software will allow molecular designers to create new small molecule drugs that will optimise such drug-water interactions. This, we believe, will have a significant impact on the field of molecular design, providing new routes for the creation of new medicinal drugs, with the obvious societal and economic benefits that this would imply. In addition, this tool will also allow for the rationalisation of the appearance of drug resistance. Our proposed software will allow the industrial molecular designer to see exactly how the protein mutations lead to a drop in drug efficacy, thereby allowing the designer to construct a computational screen, and to have the mechanistic insight to suggest modifications to the drug that would overcome resistance. This would allow owners of patents of now less-effective drugs to re-examine the causes for the loss of efficacy, and in the best case, create subtle derivatives of those drugs that overcome resistance and lead to a resurgence of that drugs saleability. The ability to revisit and update old drugs clearly has the potential for significant positive societal and economic benefits. Finally, this software will be applicable outside of the field of medicinal drug design, and could be used to rationalise any form of small molecule molecular association, e.g. to rationalise free energy flow in binding of receptors to signalling proteins, or the specific interactions of small molecules passing through channels or interaction with nanoparticles. This provides new and exciting capabilities for molecular designers across a wide range of biomedical and bioengineering disciplines, providing those designers with new, chemical-level quantitative insight coupled to a near-real time graphical design interface. This will support the process of molecular design across this wide range of disciplines enabling it to become significantly quicker, easier and more successful. Molecular design, and particular molecular design targeted at molecular association with biomolecules, provides perhaps one of the most exciting and dynamic endeavours for 21st century science, with significant potential to have wide-ranging and disruptive impact on the industries and societies of tomorrow. By creating intuitive, molecular-level graphical analysis software, we plan to make the process of molecular design significantly easier, which we hope, will help realise the grand potential of this field more quickly. Recent advances in computational hardware, software and algorithms enable simulations of protein-ligand complexes to achieve timescales during which complete ligand binding and unbinding pathways can be observed. While observation of such events can promote understanding of binding and unbinding pathways, it does not alone provide information about the molecular drivers for protein-ligand association, nor guidance on how a ligand could be optimised to better bind to the protein. We have developed the WaterSwap (C. J. Woods et al., J. Chem. Phys., 2011, 134, 054114) absolute binding free energy method that calculates binding affinities by exchanging the ligand with an equivalent volume of water. A significant advantage of this method is that the binding free energy is calculated using a single reaction coordinate from a single simulation. This has enabled the development of new visualisations of binding affinities based on free energy decompositions to per-residue and per-water molecule components. These provide a clear picture of which protein-ligand interactions are strong, and which active site water molecules are stabilised or destabilised upon binding. Optimisation of the algorithms underlying the decomposition enables near-real-time visualisation, allowing these calculations to be used either to provide interactive feedback to a ligand designer, or to provide run-time analysis of protein-ligand molecular dynamics simulations. |
| First Year Of Impact | 2013 |
| Sector | Chemicals,Digital/Communication/Information Technologies (including Software),Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Description | Research data and policy |
| Geographic Reach | National |
| Policy Influence Type | Contribution to new or improved professional practice |
| URL | https://www.chemistryworld.com/news/ukri-finds-itself-in-hot-water-too-over-researchfish-cyberbullyi... |
| Description | UKRI research data capture approaches |
| Geographic Reach | National |
| Policy Influence Type | Contribution to new or improved professional practice |
| URL | https://www.researchprofessionalnews.com/rr-news-uk-research-councils-2023-1-researchfish-tweets-aga... |
| 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 | Oracle for Research Cloud Fellowship |
| Amount | $100,000 (USD) |
| Organisation | Oracle Corporation |
| Sector | Private |
| Country | United States |
| Start | 02/2023 |
| End | 12/2023 |
| Description | PREDACTED Predictive computational models for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Desig |
| Amount | € 2,482,332 (EUR) |
| Funding ID | 101021207 |
| Organisation | European Research Council (ERC) |
| Sector | Public |
| Country | Belgium |
| Start | 10/2021 |
| End | 09/2026 |
| 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 |
| Description | https://gtr.ukri.org/person/2A2990B1-E1E1-4888-8848-7C256C3A3B43 |
| Amount | £20,009,000 (GBP) |
| Funding ID | https://gtr.ukri.org/person/2A2990B1-E1E1-4888-8848-7C256C3A3B43 |
| Organisation | United Kingdom Research and Innovation |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2006 |
| End | 02/2033 |
| Description | Catalysis Hub |
| Organisation | Research Complex at Harwell |
| Department | UK Catalysis Hub |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Modelling and simulation of enzyme mechanisms for applications in biocatalysts via the Catalysis Hub |
| Collaborator Contribution | Modelling and simulation of enzyme mechanisms for applications in biocatalysts via the Catalysis Hub and training of Hub PDRAs. |
| Impact | Catalysis is a core area of contemporary science posing major fundamental and conceptual challenges, while being at the heart of the chemical industry - an immensely successful and important part of the overall UK economy (generating in excess of £50 billion per annum). UK catalytic science currently has a strong presence, but there is intense competition in both academic and industrial sectors, and a need for UK industrial activity to shift towards new innovative areas posing major challenges for the future. In light of these challenges the UK Catalysis Hub endeavours to become a leading institution, both nationally and internationally, in the field and acts to coordinate, promote and advance the UK catalysis research portfolio. With a strong emphasis on effective use of the world-leading facilities on the RAL campus. Structure The project has four mature themes and a fifth theme starting in 2015 , each with a lead investigator as PI - Catalysis by Design (Catlow); Energy (Hardacre); Environment (Hutchings); Chemical Transformations (Davidson) and the new Biocatalysis and Biotransformations (Nick Turner Manchester) - with the design theme based in the Harwell hub. Each theme is supported by £3 - 3.5M EPSRC funding over 5 years and within each theme there are typically six to eight sub-projects funded initially for 2 years, involving collaborative teams working at a variety of sites throughout the UK. Professor Hutchings acts as director of the whole national programme for the first three year period and chairs the management group, which is supported by a steering group and an industrial advisory panel. We note that engagement with industry is one of the key aims of the catalysis hub project. As well as hosting the design theme, the centre within the Research Complex at Harwell (RCaH) will coordinate the programme, be a base for national and international visitors and provide both training and outreach activities. |
| Start Year | 2015 |
| 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 | 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 |