Abstract
The Anton supercomputing technology recently developed for efficient molecular dynamics simulations permits us to examine micro- to milli-second events at full atomic resolution for proteins in explicit water and lipid bilayer. It also permits us to investigate to what extent the collective motions predicted by network models (that have found broad use in molecular biophysics) agree with those exhibited by full-atomic long simulations. The present study focuses on Anton trajectories generated for two systems: the bovine pancreatic trypsin inhibitor, and an archaeal aspartate transporter, GltPh. The former, a thoroughly studied system, helps benchmark the method of comparative analysis, and the latter provides new insights into the mechanism of function of glutamate transporters. The principal modes of motion derived from both simulations closely overlap with those predicted for each system by the anisotropic network model (ANM). Notably, the ANM modes define the collective mechanisms, or the pathways on conformational energy landscape, that underlie the passage between the crystal structure and substates visited in simulations. In particular, the lowest frequency ANM modes facilitate the conversion between the most probable substates, lending support to the view that easy access to functional substates is a robust determinant of evolutionarily selected native contact topology.
Highlights
Proteins undergo continual conformational changes under physiological conditions while maintaining their overall fold
Our analysis clearly shows that the Anisotropic Network Model (ANM) successfully captures the global dynamics of both systems obtained by these extensive molecular dynamics (MD) simulations, while these simulations themselves may have their own limitations
We presented detailed analyses of the dynamics and conformational transitions of bovine pancreatic trypsin inhibitor (BPTI) and GltPh in comparison to the collective motions predicted by the ANM
Summary
Proteins undergo continual conformational changes under physiological conditions while maintaining their overall fold. These changes vary from local fluctuations to large scale domain/subunit movements. Typically over timescales of up to tens of nanoseconds, can be efficiently modeled by all-atom simulations; whereas global transitions, which usually occur over microseconds or slower, are largely beyond the capacity of full-atomic simulations. The latter class of motions is usually of interest due to its direct relevance to biological function. We analyze two Anton-generated trajectories, one longer than a millisecond on the equilibrium dynamics of bovine pancreatic trypsin inhibitor (BPTI), and the other, of several microseconds, on the gating mechanism of a transporter, the archaeal aspartate transporter GltPh11 that serves as a model for human excitatory amino acid transporters. Our analysis clearly shows that the ANM successfully captures the global dynamics of both systems obtained by these extensive MD simulations, while these simulations themselves may have their own limitations
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