Fast Equilibration of Water between Buried Sites and Bulk by MD with Parallel Monte Carlo Water Moves on GPUs

Abstract

Molecular dynamics (MD) simulations of proteins are commonly used to sample from the Boltzmann distribution of conformational states, with wide-ranging applications spanning chemistry, biophysics, and drug discovery. However, MD can be inefficient at equilibrating water occupancy for buried cavities in proteins that are inaccessible to the surrounding solvent. Indeed, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD, which typically ranges to hundreds of nanoseconds to low microseconds. We recently introduced a hybrid Monte Carlo/MD (MC/MD) method, which speeds up the equilibration of water between buried cavities and the surrounding solvent, while sampling from the thermodynamically correct distribution of states. While the initial implementation of the MC functionality led to considerable slowing of the overall simulations, here we address this problem with a parallel MC algorithm implemented on graphical processing units (GPUs). This results in speedups of 10-fold to 1000-fold over the original MC/MD algorithm, depending on the system and simulation parameters. The present method is available for use in the AMBER simulation software.

Structural Investigations and Binding Mechanisms of Oseltamivir Drug Resistance Conferred by the E119V Mutation in Influenza H7N9 Virus

“…The assisted model building and energy refinement 18 (Amber 18) graphic processing unit (GPU) of PMEMD was implemented in the molecular dynamic simulations of both complexes. The Amber FF14SB was employed in handling the force field related parameters and protein description [ 30 ]. The LEAP module implementation of Amber18 was also used to add hydrogen atoms to the receptor and counter-ion for neutralisation of the system [ 31 ].…”