Molecular dynamics simulations demonstrate the regulation of DNA‐DNA attraction by H4 histone tail acetylations and mutations

Abstract

The positively charged N-terminal histone tails play a crucial role in chromatin compaction and are important modulators of DNA transcription, recombination, and repair. The detailed mechanism of the interaction of histone tails with DNA remains elusive. To model the unspecific interaction of histone tails with DNA, all-atom molecular dynamics (MD) simulations were carried out for systems of four DNA 22-mers in the presence of 20 or 16 short fragments of the H4 histone tail (variations of the 16-23 a. a. KRHRKVLR sequence, as well as the unmodified fragment a. a.13-20, GGAKRHRK). This setup with high DNA concentration, explicit presence of DNA-DNA contacts, presence of unstructured cationic peptides (histone tails) and K(+) mimics the conditions of eukaryotic chromatin. A detailed account of the DNA interactions with the histone tail fragments, K(+) and water is presented. Furthermore, DNA structure and dynamics and its interplay with the histone tail fragments binding are analysed. The charged side chains of the lysines and arginines play major roles in the tail-mediated DNA-DNA attraction by forming bridges and by coordinating to the phosphate groups and to the electronegative sites in the minor groove. Binding of all species to DNA is dynamic. The structure of the unmodified fully-charged H4 16-23 a.a. fragment KRHRKVLR is dominated by a stretched conformation. The H4 tail a. a. fragment GGAKRHRK as well as the H4 Lys16 acetylated fragment are highly flexible. The present work allows capturing typical features of the histone tail-counterion-DNA structure, interaction and dynamics.

Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions

“…More recently, Collepardo-Guevara et al in a multiscale simulations showed that lysine acetylation increased secondary-structure content within the histone tail and decreased tail availability for crucial fiber compacting internucleosome interactions [54], consistent with earlier simulations of conformational ensemble of fragments of histone tails without DNA in solution [55, 56]. These results are also in line with the previous simulations of DNA interactions with H4-tail peptides [57, 58], which suggested that charged groups of arginines and lysines play major roles in the tail-mediated DNA-DNA attraction by forming bridges with phosphates and interacting with electronegative sites in the minor groove.…”

A Coarse-Grained DNA Model Parameterized from Atomistic Simulations by Inverse Monte Carlo

“…Simulations were run for 40 ns collecting atom coordinates with 1 ps resolution. Detailed description of the simulations and major results are reported in our earlier work [76].…”

Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A Multiscale Computational Study

“…12 ) provide detailed views, as well as mechanistic and thermodynamic information, complementing experiments that might lack the spatial resolution to provide a molecular perspective of the problem. Hardware and software advances have allowed several all-atom sim-ulations of isolated histone tails 13 , tails with DNA 13a, 14 , and even nucleosomes 15 with explicit solvent and ions. All-atom molecular dynamics (MD) simulations in both implicit 16 and explicit solvent 13b suggested that the histone tail peptides are not fully disordered.…”