Nucleosome binding peptide presents laudable biophysical and in vivo effects

Kaian Teles,Vinicius Fernandes,Isabel Silva,Manuela Leite,Cesar Grisolia,Vincenzo R Lobbia,Hugo Van Ingen,Rodrigo Honorato,Paulo Lopes-De-Oliveira,Werner Treptow,Guilherme Santos

doi:10.1016/j.biopha.2019.109678

Abstract

Chromatin state is highly dependent on the nucleosome binding proteins. Herein, we used a multipronged approach employing biophysical and in vivo experiments to characterize the effects of Nucleosome Binding Peptides (NBPeps) on nucleosome and cell activity. We performed a series of structure-based calculations on the nucleosome surface interaction with GMIP1 (a novel NBPep generated in silico), and HMGN2 (nucleosome binding motif of HMGN2), which contains sites that bind DNA and the acid patch, and also LANA and H4pep (nucleosome binding motif of H4 histone tail) that only bind to the acidic patch. Biochemical assays shows that H4pep, but not HMGN2, GMIP1 and LANA, is highly specific for targeting the nucleosome, with important effects on the final nucleosome structure and robust in vivo effects. These findings suggest that NBPeps might have important therapeutic implications and relevance as tools for chromatin investigation.

Highlights

Chromatin is a macromolecular complex composed of distinct molecules
AutoDock Vina was used to resolve peptide binding to the acidic patch region of nucleosome core particle (NCP) [18]
Solutions were clustered in 15–17 structural groups based on a maximum neighborhood criterion and the group with best fit to the acidic patch was chosen for further simulation

Summary

Introduction

Chromatin is a macromolecular complex composed of distinct molecules. Basic proteins (histone octamer) interact with DNA to form the nucleosome core particle (NCP), generating the fundamental repetitive unit of chromatin. The NCP represents the first level of DNA compaction, followed by a cooperative nucleosome interaction to form the higher-order chromatin structure (reviewed in [1]). Chromatin dynamics, which is controlled by a plethora of Nucleosome Binding Proteins (NBPs), is essential for genome integrity and gene expression regulation. From condensed to relaxed chromatin, NBPs may induce specific modifications of chromatin architecture dependent on their unique properties [2]. In addition to NBPs, the nuclear environment comprises many small molecules with different chemical natures that can directly interact with nucleosomes, such as Mg2+ and lipids [3,4]

Methods

Results

Conclusion