Average and extreme multi-atom Van der Waals interactions: Strong coupling of multi-atom Van der Waals interactions with covalent bonding

Abstract

Background: The prediction of ligand binding or protein structure requires very accurate force field potentials - even small errors in force field potentials can make a 'wrong' structure (from the billions possible) more stable than the single, 'correct' one. However, despite huge efforts to optimize them, currently-used all-atom force fields are still not able, in a vast majority of cases, even to keep a protein molecule in its native conformation in the course of molecular dynamics simulations or to bring an approximate, homology-based model of protein structure closer to its native conformation. Results: A strict analysis shows that a specific coupling of multi-atom Van der Waals interactions with covalent bonding can, in extreme cases, increase (or decrease) the interaction energy by about 20-40% at certain angles between the direction of interaction and the covalent bond. It is also shown that on average multi-body effects decrease the total Van der Waals energy in proportion to the square root of the electronic component of dielectric permittivity corresponding to dipoledipole interactions at small distances, where Van der Waals interactions take place. Conclusion: The study shows that currently-ignored multi-atom Van der Waals interactions can, in certain instances, lead to significant energy effects, comparable to those caused by the replacement of atoms (for instance, C by N) in conventional pairwise Van der Waals interactions.