Mapping Allosteric Communication in the Nucleosome with Conditional Activity

Abstract

The nucleosome core particle (NCP) regulates genome accessibility through dynamic allosteric communication between histone proteins and DNA. Building on the concept of conditional activity introduced by Lin (2016), we use molecular dynamics simulations and develop an open-source Python library, CONDACT (CONDitional ACTivity), to quantify time-resolved kinetic correlations in nucleosome systems. We analyze long-time simulations of the nucleosome core particle, including two different DNA sequences, the Widom-601 and ASP (alpha-satellite palindromic) sequences. By tracking dihedral angle transitions, we identify residues with high dynamical memory and map inter-residue communication pathways across histone subunits and DNA. Our analysis reveals kinetically connected domains involving post-translational modification sites, oncogenic mutation sites, and DNA contact regions, with dynamic coupling observed over distances up to 7.5 nm. These findings offer new insight into the long-range allosteric behavior of the nucleosome and its potential role in regulating chromatin accessibility. Quantifying this allosteric behavior potentially identifies targetable residues and domains for therapeutic intervention. Statement of SignificanceThe nucleosome regulates DNA accessibility and plays a key role in epigenetic control of gene expression, yet the kinetic mechanism by which local modifications influence distant regions remains poorly understood. Here, we identify kinetically coupled domains that include post-translational modification and oncogenic mutation sites. We uncover networks of allosteric signaling pathways that provide fundamental insight into how the nucleosome communicates.