Exploring the Free Energy Landscape of Nucleosomes

Abstract

The nucleosome is the fundamental unit for packaging the genome. A detailed molecular picture for its conformational dynamics is crucial for understanding transcription and gene regulation. We investigate the disassembly of single nucleosomes using a predictive coarse-grained protein DNA model with transferable force fields. This model quantitatively describes the thermodynamic stability of both the histone core complex and the nucleosome and predicts rates of transient nucleosome opening that match experimental measurements. Quantitative characterization of the free-energy landscapes reveals the mechanism of nucleosome unfolding in which DNA unwinding and histone protein disassembly are coupled. The interfaces between H2A-H2B dimers and the (H3-H4)2 tetramer are first lost when the nucleosome opens releasing a large fraction but not all of its bound DNA. For the short strands studied in single molecule experiments, the DNA unwinds asymmetrically from the histone proteins, with only one of its two ends preferentially exposed. The detailed molecular mechanism revealed in this work provides a structural basis for interpreting experimental studies of nucleosome unfolding.

A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R

“…Obtaining realistic free‐energy landscapes that describe the function of biological system proved useful in previous studies . However, specifically for GPCRs progress has been limited, as discussed by Deupi and Kobilka .…”

“…Obtaining realistic free-energy landscapes that describe the function of biological system proved useful in previous studies. [38][39][40][41] However, specifically for GPCRs progress has been limited, as discussed by Deupi and Kobilka. 42 To this end, in our previous β 2 AR study 37 we modeled and constructed all the end-point conformations of the G protein (considering the interdomain orientation and the order/disorder state of the C-terminal α5) and receptor, including all complexes.…”

Molecular Mechanism of Facilitated Dissociation of Fis Protein from DNA

“…This model has been previously applied to study molecular stripping of NF κ B from DNA by I κ B 12 and the disassembly of the nucleosome. 15 Although Fis protein does exhibit sequence specific binding, its preferred 15 base pair core recognition signal is poorly conserved and thus its sequence specificity is weak. 4,16,17 The major part of the binding of Fis protein to DNA in the simulation comes from nonspecific electrostatic interactions which can be modeled using Debye–Hückel potentials.…”

Autoinhibition can identify rare driver mutations and advise pharmacology

“…[40][41][42][43][44][45][46][47][48][49][50][51][52] The landscape is not static. [40][41][42][43][44][45][46][47][48][49][50][51][52] The landscape is not static.…”