Inferring coarse-grain histone-DNA interaction potentials from high-resolution structures of the nucleosome

TL;DR

This study develops a nanoscale force-field model for histone-DNA interactions in nucleosomes, derived from structural data, revealing repulsive forces and DNA tension that influence nucleosome stability and DNA binding preferences.

Contribution

It introduces the first knowledge-based nanoscale potential for histone-DNA interactions, derived from high-resolution structures and simulations, applicable to various protein-DNA complexes.

Findings

DNA base-pairs are locally shifted outwards at contact sites.

A sequence-independent quadratic repulsive force field explains local force profiles.

Repulsive forces relate to DNA stretch tension, affecting nucleosome stability.

Abstract

The histone-DNA interaction in the nucleosome is a fundamental mechanism of genomic compaction and regulation, which remains largely unkown despite a growing structural knowledge of the complex. Here, we propose a framework for the extraction of a nanoscale histone-DNA force-field from a collection of high-resolution structures, which may be adapted to a larger class of protein-DNA complexes. We apply the procedure on a large crystallographic database extended by snapshots from molecular dynamics simulations. The comparison of the structural models first shows that, at the sites of histone-DNA contact, the DNA base-pairs are locally shifted outwards, consistent with locally repulsive forces exerted by the histones. In a second step, we show that the various force profiles of the analyzed structures derive locally from a unique, sequence-independent, quadratic repulsive force field, while the sequence preferences are entirely due to the internal DNA mechanics. We thus obtain the first knowledge-derived nanoscale potential for the histone-DNA interaction in the nucleosome. The conformations obtained by relaxation of nucleosomal DNA with high-affinity sequences in this potential accurately reproduce experimental values of binding preferences. We finally address the more generic binding mechanisms relevant to the 80% genomic sequences incorporated in nucleosomes, by computing the conformation of nucleosomal DNA with sequence-averaged properties. This conformation is found to differ from those found in crystals, and the analysis suggests that repulsive histone forces are related to a local stretch tension in nucleosomal DNA, mostly between successive contact points. This tension could play a role in the stability of the complex.