Abba E. Leffler
D.E. Shaw Research
March 22, 2011
Applications of long-timescale molecular dynamics simulation to protein function and folding
Long-timescale Molecular Dynamics (MD) simulations have the potential to advance our understanding of a variety of biological phenomena by characterizing the conformational changes of proteins associated with those processes in atomic detail. Simulations executed with a high-performance MD code, Desmond, and special-purpose supercomputer, Anton, developed at D. E. Shaw Research enable microsecond timescale simulations with tens of thousands of atoms to be routinely performed. Anton has also made possible a millisecond long simulation, which is two orders of magnitude longer than the previous record for an all-atom MD protein simulation. Several results recently attained using Desmond and Anton concerning the folding of small proteins and function of ion channels have implications for protein design and engineering. (1) Simulations of a fast-folding, beta-sheet protein domain, the WW domain, demonstrate that its folding follows a single, well-defined pathway in which its various elements of secondary structure form in a specific order. The nature of the transition state was also determined, showing that the first, but not second, element of secondary structure that forms is present in the transition state. These results have led to engineering of the fastest folding protein with beta-sheet content currently known. (2) Simulations of the open, conducting pore domain of the voltage-gated potassium channel Kv1.2 at depolarizing potentials reveal a permeation mechanism resembling the Hodgkin-Keynes "knock-on" model, in which translocation of ions already present in the selectivity filter of the pore is driven by an incoming ion. At hyperpolarizing potentials, the pore closes after several microseconds due to a "hydrophobic-gating" mechanism: the pore collapses into a closed state, after ions and waters are driven out of its cavity, due to the presence of highly conserved hydrophobic residues that line the cavity. The role that these residues play in the transition of the pore from open to closed suggests mutations that can be introduced into the channel to facilitate crystallizing it in the closed state. With the advent of even longer MD simulations of larger systems, the range of biological problems to which MD can be applied continues to expand.