Molecular dynamics (MD) simulations of proteins cannot efficiently equilibrate water occupancy in buried cavities, leading to slow convergence of thermodynamic averages. This becomes particularly problematic for protein-ligand binding free energy calculations when the ligand is in a buried site, as standard MD cannot account for changes in hydration when a ligand is either changed alchemically or fully decoupled from the site. Several prior works have addressed this problem by integrating grand canonical Monte Carlo (MC) steps with MD simulations, so that water molecules can be added to, or removed from, random locations in the system. However, the grand canonical method adds algorithmic complexity, particularly as it leads to changes in the numbers of water molecules in the course of a simulation. We have addressed this challenge by 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 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 energy calculation is used to reduce the number of expensive full energy calculations. We tested this new MD/MC method as follows. First, we showed that potential energies produced over 107 steps using MC/MD are not statistically different from control simulations using only MD. Second, we used MC/MD for hydrating and dehydrating buried cavities. In all four test systems MC/MD was able to properly equilibrate the water molecules, whereas normal MD failed to sample the correct state. We anticipate that a key application of this technology will be to accelerate protein-ligand binding free energy calculations involving buried binding sites. The method is available in the widely disseminated AMBER18 simulation package.

Equilibration of buried water molecules to enhance protein-ligand binding free energy calculations

2019 Fall National Meeting

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