Inquire: Software for real-time analysis of binding

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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.