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Inquire: Software for real-time analysis of binding

Reference	BB/K016601/1
Principal Investigator / Supervisor	Professor Adrian Mulholland
Co-Investigators / Co-Supervisors	Dr Christopher Woods
Institution	University of Bristol
Department	Chemistry
Funding type	Research
Value (£)	105,748
Status	Completed
Type	Research Grant
Start date	05/09/2013
End date	04/09/2014
Duration	12 months

Abstract

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.

Summary

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 interestedin 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.

Impact Summary

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.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Pharmaceuticals, Structural Biology, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	Tools and Resources Development Fund (TRDF) [2006-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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