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Simulating Water Exchange to Buried Binding Sites.pdf (1.38 MB)

Simulating Water Exchange to Buried Binding Sites

submitted on 20.12.2018, 21:45 and posted on 21.12.2018, 15:47 by Ido Ben-Shalom, charles Lin, Tom Kurtzman, ross walker, Michael Gilson
Traditional molecular dynamics (MD) simulations of proteins, which rely on integration of Newton’s equations of motion, cannot efficiently equilibrate water occupancy for buried cavities in proteins. This leads to slow convergence of thermodynamic averages for such systems. We have addressed this challenge by efficiently integrating standard Metropolis Monte Carlo (MC) translational water moves with MD in the AMBER simulation package. The translational moves allow water to easily enter or exit buried sites in a thermodynamically correct way during a simulation. To maximize efficiency, the algorithm avoids moves that only interchange waters within the bulk around the protein, instead focusing on moves that can transfer water between bulk and the protein interior. In addition, a steric grid allows avoidance of moves that would lead to obvious steric clashes, and a fast grid-based energy evaluation is used to reduce the number of expensive full energy calculations. The potential energy distribution produced using MC/MD was found to be statistically indistinguishable from that of control simulations using only MD, and the algorithm effectively equilibrated water across steric barriers and into binding pockets that are not accessible with pure MD. The MC/MD method introduced here should be of increasing utility for applications spanning protein folding, the elucidation of protein mechanisms, and free energy calculations for computer-aided drug design. It is available in version 18 release of the widely disseminated AMBER simulation package.


MKG acknowledges funding from National Institute of General Medical Sciences (GM061300 and GM100946). RCW and CL thanks Intel and their Parallel Computing Center for support.


Email Address of Submitting Author


University of California, San Diego


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

MKG has an equity interest in and is a cofounder and scientific advisor of VeraChem LLC. GSK did not fund this work and the authors declare no competing interest.