Exploring atomic resolution physiology on a femtosecond to millisecond timescale using molecular dynamics simulations

Ron O. Dror, Morten Ø. Jensen, David W. Borhani, David E. Shaw
2010 The Journal of General Physiology  
Discovering the functional mechanisms of biological systems frequently requires information that challenges the spatial and temporal resolution limits of current experimental techniques. Recent dramatic methodological advances have made all-atom molecular dynamics (MD) simulations an ever more useful partner to experiment because MD simulations capture the atomic resolution behavior of biological systems on timescales spanning 12 orders of magnitude, covering a spatiotemporal domain where
more » ... mental characterization is often difficult if not impossible. We present here our perspective on the mechanistic insights that a scientistin particular, a membrane protein physiologist-might garner by complementing experiments with atomistic MD simulations. Drawing on case studies from our work, we illustrate the diversity of membrane proteins amenable to study by MD and the types of discoveries one can make through simulation. We discuss the strengths and limitations of MD as a tool for physiologists, and we speculate on advances that such simulations may enable in the coming years. Why simulate? What might a physiologist gain by supplementing the usual experimental tools-cell lines, patch clamp rig, spectrometers, and the like-with atomistic MD simulations? Foremost is the ability to probe the biological system of interest, which may be anything from an individual protein to a large biological assembly, across a very broad range of timescales at high spatial resolution (Fig. 1 ). An all-atom MD simulation typically comprises thousands to millions of individual atoms representing, for example, all the atoms of a membrane protein and of the surrounding lipid bilayer and water bath (Fig. 2) . The simulation progresses in a series of short, discrete time steps; the force on each atom is computed at each time step, and the position and velocity of each atom are then updated according to Newton's laws of motion. Each atom in the system Correspondence to David E. Shaw: David.Shaw@DEShawResearch.com Abbreviations used in this paper: AQP0, aquaporin 0;  2 AR,  2 -adrenergic receptor; GPCR, G protein-coupled receptor; MD, molecular dynamics. under study is thus followed intimately: its position in space, relative to all the other atoms, is known at all times during the simulation. This exquisite spatial resolution is accompanied by the unique ability to observe atomic motion over an extremely broad range of timescales-12 orders of magnitude-from 1 femtosecond (10 15 s), less than the time it takes for a chemical bond to vibrate, to >1 ms (10 3 s), the time it takes for some proteins to fold, for a substrate to be actively transported across a membrane, or for an action potential to be initiated by the opening of voltage-gated sodium channels. MD simulations thus allow access to a spatiotemporal domain that is difficult to probe experimentally (Fig. 1) . Simulations can be particularly valuable for membrane proteins, for which experimental characterization of structural dynamics tends to be challenging. How might this ability to "see" the atoms of a biological system moving over time truly be useful? First, one can observe qualitative behavior, such as the mechanism of permeation through membrane channels. Second, one can probe systems quantitatively, for example, determining the conductance of a single water or ion channel (Fig. 2) . Third, simulations often allow one to generate novel mechanistic hypotheses, sometimes based simply on straightforward observation: as Yogi Berra once said, "You can observe a lot by watching." Fourth, simulations of perturbed or mutated molecular systems can be used to test specific hypotheses originating from experiment, computation, or theory. The power of MD simulations is further augmented by the ability to model molecules that cannot easily be constructed experimentally. A wide variety of physiological processes are amenable to study at the atomic level by MD simulation. Examples relevant to membrane protein function include the active transport of solutes across bilayers by antiporters and symporters; the passive transport of water, ions, Perspectives on: Molecular dynamics and computational methods
doi:10.1085/jgp.200910373 pmid:20513757 pmcid:PMC2888062 fatcat:yqbrpjcg3ravziupmkjk6wff7m