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Biomolecular Solvation Structure Revealed by Molecular Dynamics Simulations

revised on 12.02.2019 and posted on 13.02.2019 by Michael Wall, Gaetano Calabró, Christopher I. Bayly, David Mobley, Gregory Warren
To compare ordered water positions from experiment with those from molecular dynamics (MD) simulations, a number of MD models of water structure in crystalline endoglucanase were calculated. The starting MD model was derived from a joint X-ray and neutron diffraction crystal structure, enabling the use of experimentally assigned protonation states. Simulations were performed in the crystalline state, using a periodic 2x2x2 supercell with explicit solvent. Water X-ray and neutron scattering density maps were computed from MD trajectories using standard macromolecular crystallography methods. In one set of simulations, harmonic restraints were applied to bias the protein structure toward the crystal structure. For these simulations, the recall of crystallographic waters using strong peaks in the MD water electron density was very good, and there also was substantial visual agreement between the boomerang-like wings of the neutron scattering density and the crystalline water hydrogen positions. An unrestrained simulation also was performed. For this simulation, the recall of crystallographic waters was much lower. For both restrained and unrestrained simulations, the strongest water density peaks were associated with crystallographic waters. The results demonstrate that it is now possible to recover crystallographic water structure using restrained MD simulations, but that it is not yet reasonable to expect unrestrained MD simulations to do the same. Further development and generalization of MD water models for force field development, macromolecular crystallography, and medicinal chemistry applications is now warranted. In particular, the combination of room-temperature crystallography, neutron diffraction, and crystalline MD simulations promises to substantially advance modeling of biomolecular solvation.


The New Mexico Small Business Assistance Program

University of California Laboratory Fees Research Program

US Department of Energy Exascale Computing Project (17-SC-20-SC)


Email Address of Submitting Author


Los Alamos National Laboratory



ORCID For Submitting Author


Declaration of Conflict of Interest

David Mobley serves on the Scientific Advisory Board of OpenEye Scientific Software, and is an Open Science Fellow with Silicon Therapeutics

Version Notes

Revised submitted manuscript.