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Biology from First Principles?

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One of the challenges confronting biology is to move from a qualitative understanding of biological systems to a quantitative understanding. The Genome Project has, in principle, provided us with all the input information necessary to model biological systems. Systems Biology is addressing the question of how resilient yet adaptive systems, characteristic of living cells and organisms, arise from the complex web of interactions between the component parts. The relationship between the Genome and System Biology is extraordinarily complex but this relationship is ultimately determined by the atomistic scale behaviour of the components of the biological system. In this respect, biology is no different from many systems in the physical sciences where the behaviour of systems is ultimately determined by the processes that occur at the atomic scale. It is now known, from extensive experience in these physical sciences, that the behaviour at the atomistic scale can be accurately predicted using parameter free quantum mechanical calculations based on density functional theory. These calculations are often referred to as first principles or ab initio. For instance, such first principles calculations have provided an understanding of the molten core of the earth [1], of chemical reactions in numerous different environments [for examples see 2,3], of the growth of oxide films on aluminium [4] and silicon [5] surfaces and there many thousands of other applications. These applications provide a glimpse of the potential impact of quantum mechanical modelling in biology. For instance, our simulations of the reaction of methanol in zeolites [3] showed that, despite decades of research, none of the existing models of the behaviour of this system was correct. This begs the question If we are unable to correctly predict the behaviour of a few tens of atoms in a very well defined configuration what is the chance that we can genuinely predict the atomic scale behaviour of biological systems? While motivating a need for first principles simulations in biology, the system sizes and timescales needed to study biological problems make the application of first principles techniques extraordinarily challenging. In this talk I shall first outline some successful applications of first principles calculations to biological problems. I shall then describe two computational techniques we are currently developing that, we hope, will make first principles calculations on biological systems accessible to all researchers. The first of these techniques is ONETEP , a density functional theory code whose computational cost scales linearly with the number of atoms in the system. ONETEP allows first principles calculations to be routinely performed on systems containing many thousands of atoms. The second of these techniques is a hybrid or QM/MM modelling scheme which we are developing in collaboration with Dr. De Vita of Kings College, London. What makes our hybrid scheme special is that the choice of which atoms should be treated quantum mechanically can be delegated to the computer and is allowed to vary during the simulation.

References [1] D. Alfe, M.J. Gillan and G.D. Price, Nature 401, 462 (1999).

[2] A. De Vita, I. Stich, M.J. Gillan, M.C. Payne and L.J. Clarke, Phys.Rev.Lett. 71 1276 (1993).

[3] I. Stich, J.D. Gale K. Terakura and M.C. Payne, Chem.Phys.Lett. 283, 402 (1998)

[4] L.C. Ciacchi and M.C. Payne, Phys.Rev.Lett 92, 176104 (2004).

[5] L.C. Ciacchi and M.C. Payne, Phys.Rev.Lett 95, 196101 (2005).

This talk is part of the Modelling Biology series.

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