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.

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.

Publications

10 25 50
 
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 2014
Sector Chemicals,Digital/Communication/Information Technologies (including Software),Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
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 Academic/University
Country United Kingdom
Start 01/2015 
End 12/2019
 
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 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