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

Discovering the functional mechanisms of biological systems frequently requires information that challenges the spatial and temporal resolution limits of current experimental techniques. Recent dramatic methodologi-cal 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 spatiotem-poral domain where experimental characterization is often difficult if not impossible. We present here our perspective on the mechanistic insights that a scientist— in 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. What might a physiologist gain by supplementing the usual experimental tools—cell lines, patch clamp rig, spectrometers, and the like—with atomistic MD simu-lations? 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 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 …