CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface

"Everything that living things do can be understood in terms of the jigglings and wigglings of atoms" as Richard Feynman provocatively stated nearly fifty years ago. But how can we 'see' this wiggling and jiggling and understand how it drives biology? Increasingly, computer simulations of biological macromolecules are helping to meet this challenge. Experiments can provide detailed structures of biological macromolecules such as proteins, but it is hard to study directly how the structures of individual molecules change on short timescales as they function. Similarly it is not yet possible to study directly by experiment alone the molecular mechanisms of fast processes such as chemical reactions in enzymes or ion transport through membranes. Simulations based on fundamental physics offer the potential of filling-in these crucial 'gaps', modelling how proteins and other biomolecules move, fluctuate, interact, react and function.
Physics-based simulations complement experiments in building a molecular level understanding of biology: they can test hypotheses and interpret and analyse experimental data in terms of interactions at the atomic level. A wide variety of simulation techniques have been developed, applicable to a range of different problems in biomolecular science. Simulations have already shown their worth in helping to analyse how enzymes catalyse biochemical reactions, and how proteins adopt their functional structures. They can help in the design of drugs and catalysts, and in understanding the molecular basis of disease. And simulations have played a key role in developing the conceptual framework now at the heart of biomolecular science, that is, the understanding that the way that biological molecules move and flex - their dynamics - is central to their function, demonstrating the truth of Feynman's assertion.
Developing methods from chemical physics and computational science will open exciting new opportunities in biomolecular science, including in drug design and development, synthetic biology, biotechnology and biocatalysis. Much biomolecular simulation demands HEC resources: e.g. large-scale simulations of biological machines such as the ribosome, proton pumps and motors, membrane receptor complexes and even whole viruses. A particular challenge is the integration of simulations across length and timescales: different types of simulation method are required for different types of problems). We work to develop 'multiscale' modelling and simulation methods to tackle these large problems, in areas such as drug metabolism and transport.

Biomolecular simulation and modelling is vital e.g. to the pharmaceutical industry, where it is an integral part of drug design and development (e.g. in structure-based drug design and predictions of drug metabolism). Pharma needs well-trained scientists in this area, and new methods (e.g. for prediction of drug binding affinities). CCP-BioSim contributes directly to both of these key requirements. Our activities also promote collaboration between simulation and experiment; biomolecular simulation is central to multidisciplinary research programmes. CCP-BioSim, and the computational tools it develops and contributes to, increase biological applications of high-end computing (HEC). As well as biosimulation specialists, a broad community of industrial and academic bioscientists investigating biomolecular structure and function will benefit from CCP-BioSim. Longer term, CCP-BioSim has the potential to contribute to improvements in health and quality of life. The bioscience community will benefit through access to tools, training, and trained simulation specialists that enable novel and more effective multidisciplinary projects where computational methods enhance and extend their core experimental approaches. CCP-BioSim helps to train scientists able to work across the theory/experimental boundary. Impacts on health will come from the application of the methods fostered and disseminated by CCP-BioSim to drug design and discovery. CCP-BioSim will a) help to train new researchers b) develop and disseminate advanced computational methods and c) provide a forum to enhance industrial-academic research links (members of the management group have strong links with many pharmaceutical/biotech companies, e.g. AstraZeneca, Vernalis, Phaminox, GSK, Evotec, Pfizer, Sanofi, Astex, etc.). There is also broader impact of biomolecular simulation in areas such as drug delivery and synthetic biology. Finally, vast amounts of data are coming from genomics, proteomics, glycomics and structural biology. Developments in X-ray crystallography, high-throughput sequencing, protein production and crystallization, EM, SAXS, NMR and mass spectrometry, combined with modern data storage capacities have vastly increased the quantity of information available in structural biology, proteomics and genomics databases. Investment in understanding and interpretation in terms of biological function is vital to make use of this information. Biomolecular simulation is essential to enhance understanding and guide further experiments, especially as the quantity and complexity of biological data is immense and continues to grow. Improved understanding of biomolecular interactions and their consequences is not just of fundamental interest, but also benefits applied science. Progress in understanding biomacromolecules requires an integrated approach using a range of biophysical techniques, both experimental and computational. Biomolecular simulation will help to use these data to develop new drugs, catalysts and nanotechnology.