Abstract
The influence of lone-pair electrons on the directionality of hydrogen bonds that are formed by oxygen and nitrogen atoms in the side chains of nine hydrophilic was investigated using molecular dynamics simulations. The simulations were conducted using two types of force fields; one incorporated lone-pair electrons placed at off-atom sites and the other did not. The density distributions of the hydration water molecules around the oxygen and nitrogen atoms were calculated from the simulation trajectories, and were compared with the empirical hydration distribution functions, which were constructed from a large number of hydration water molecules found in the crystal structures of proteins. Only simulations using the force field explicitly incorporating lone-pair electrons reproduced the directionality of hydrogen bonds that is observed in the empirical distribution functions for the deprotonated oxygen and nitrogen atoms in the sp2-hybridization. The amino acids that include such atoms are functionally important glutamate, aspartate, and histidine. Therefore, a set of force field that incorporates lone-pair electrons as off-atom charge sites would be effective for considering hydrogen bond formation by these amino acids in molecular dynamics simulation studies.
Highlights
Hydrogen bonds (H-bonds) play an important role in the various biomolecular processes of proteins such as protein folding, molecular recognition, and enzymatic reactions1–3
We first describe the results of restrained electrostatic potential31 (RESP) calculation for constructing force field parameters used in molecular dynamics (MD) calculations
In the RESP calculations, the oxygen and nitrogen atoms incorporating LP charge sites were polarized with negative charges present on the LP sites and positive charges located on the atom center (Table S1)
Summary
Hydrogen bonds (H-bonds) play an important role in the various biomolecular processes of proteins such as protein folding, molecular recognition, and enzymatic reactions. Most MD simulation studies use molecular mechanical force fields based on atom-centered charges (monopole electrostatic). In the implicit form, multipole electrostatic including dipole and quadrupole terms of atomic interactions is introduced into both non-polarizable and polarizable force fields25 These studies have shown that the inclusion of LP electrons improves the agreement of MD simulations with QM calculations and experimental thermodynamic quantities. In spite of these advancements, the force fields with LP electrons have been used much less often than those without LP electrons This lack of enthusiasm might be attributed to the fact that the importance of LP electrons has not been widely recognized, partly because reports of direct comparisons between simulation results and experimental information on atomic interactions such as H-bond directionality are rare. The EHDF provides experimental evidence for the geometrical characteristics of the H-bonds formed between the hydration water molecules and the hydrophilic residues
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