Atomic-Level Characterization of the Structural Dynamics of Proteins

Abstract

Molecular dynamics (MD) simulations are widely used to study protein motions at an atomic level of detail, but they have been limited to time scales shorter than those of many biologically critical conformational changes. We examined two fundamental processes in protein dynamics--protein folding and conformational change within the folded state--by means of extremely long all-atom MD simulations conducted on a special-purpose machine. Equilibrium simulations of a WW protein domain captured multiple folding and unfolding events that consistently follow a well-defined folding pathway; separate simulations of the protein's constituent substructures shed light on possible determinants of this pathway. A 1-millisecond simulation of the folded protein BPTI reveals a small number of structurally distinct conformational states whose reversible interconversion is slower than local relaxations within those states by a factor of more than 1000.

Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A

“…Additionally, with recent advances in specialized computational architectures like Anton, simulation timescales on the order of microseconds to milliseconds in a single trajectory are within reach (7,(12)(13)(14).…”

Enhanced sampling simulations to construct free-energy landscape of protein–partner substrate interaction

“…The MD technique with a general-purpose graphics processing unit (GPGPU) (Götz et al 2012;Mashimo et al 2013;Pall et al 2014;SalomonFerrer et al 2013) is growing in importance due to multiple processors being less expensive than CPUs. Hardware architectures specialized for MD, such as Anton (Shaw et al 2009) and MD-GRAPE (Narumi et al 2006), have enabled extremely long-time scale MD simulations (Kikugawa et al 2009;Lindorff-Larsen et al 2011;Shaw et al 2010). These specialized architectures speed up a single MD simulation run and provide an increased number of conformations from the long MD trajectory.…”

Molecular simulations and visualization: introduction and overview

“…Multi-core architectures are evolving quickly, with massive-parallelism and massive-threading available on machines like the 1.3 million thread Blue Waters supercomputer. Bespoke architecture development, like that available on the Anton machine, is similarly allowing researchers to push the boundaries of simulation [ 74 ] and new techniques based on cloud-based methods and ultrafast highperformance networking are just around the corner. These and likely future developments in HPC are making massively parallel computations viable, and are stimulating innovation across hardware, software, and hardware/software integration much of which is aimed at tackling the main challenges of molecular simulation: the size of systems which can be simulated, the time-scales which it is possible to simulate, the ability to sample large regions of molecular phase space, and the rigor of the underlying physics within the models.…”