Biology subjects

Loverde, S.

Publications and source records attributed to Loverde, S..

4 recordsLinked to original sources

bioRxiv2025

Mapping Allosteric Communication in the Nucleosome with Conditional Activity

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.

biophysics↗

bioRxiv2025

Structural and Thermodynamic Impact of Oncogenic Mutations on the Nucleosome Core Particle

The nucleosome core particle (NCP) is essential for chromatin structure and function, serving as the fundamental unit of eukaryotic chromatin. Oncogenic mutations in core histones disrupt chromatin dynamics, altering DNA repair and transcription processes. Here, we investigate the molecular consequences of two mutations--H2BE76K and H4R92T--using 36 {micro}s of all-atom molecular dynamics simulations and experimental biophysical assays. These mutations destabilize the H2B-H4 interface by disrupting critical salt bridges and hydrogen bonds, reducing binding free energy at this interface. Principal component analysis reveals altered helix conformations and increased interhelical distances in mutant systems. Thermal stability assays (TSA) and differential scanning calorimetry (DSC) confirm that these mutations lower the dimer dissociation temperature and reduce enthalpy compared to the wild type. Taken together, our results elucidate how these mutations compromise nucleosome stability and propose mechanisms through which they could modulate chromatin accessibility and gene dysregulation in cancer. Statement of SignificanceThe nucleosome is the essential packaging unit of DNA. Oncohistones which are histone mutations that are associated with cancer, are known to compromise the stability of the nucleosome and affect nucleosome sliding. Here we perform long-time molecular dynamics simulations of two buried histone core mutations, demonstrating that these mutations reduce the stability of the histone core at the H2B-H4 interface. Next, we demonstrate that these same mutations lower the dimer dissociation temperature and shift the nucleosome dissociation pathway.

biophysics↗

bioRxiv2025

Unveiling the Conformational Dynamics of the Histone Tails Using Markov State Modeling

Biomolecules predominantly exert their function through altering conformational dynamics. The nucleosome core particle (NCP) is the fundamental unit of chromatin. DNA with [~]146 base pairs wrap around the histone octamer to form a nucleosome. The histone octamer is comprised of two copies of each histone protein (H3, H4, H2A, and H2B) with a globular core and disordered N-terminal tails. Epigenetic modifications of the histone N-terminal tails play a critical role in the regulation of chromatin structure and biological processes such as transcription and DNA repair. Here, we report all-atomistic molecular dynamics (MD) simulations of the nucleosome at microsecond timescales to construct Markov state models (MSMs) to elucidate distinct conformations of the histone tails. We employ the time-lagged independent component analysis (tICA) to capture their essential slow dynamics, with k-means clustering used to discretize the conformational space. MSMs unveil distinct states and transition probabilities to characterize the dynamics and kinetics of the tails. Next, we focus on the H2B tail, one of the least studied tails. We show that acetylation increases secondary structure formation, with an increase in transition rates. These findings will aid in understanding the functional implications of tail conformations in nucleosome stability and gene regulation. Significance StatementThe nucleosome is the fundamental repeat unit of chromatin, composed of a histone octamer and DNA. Each histone has a globular core and N-terminal tail regions. N-terminal tails are major sites for post-translational modifications, chromatin structure, and gene regulation. Using all-atom molecular dynamics simulations of the nucleosome to examine the dynamics of histone tails and analyze the effects of one of the histone modifications, such as acetylation on histone tails. We explore tail dynamics and kinetics using Markov State Models (MSMs) to gain insight into histone tail structural changes. Acetylation of the H2B tail shows an increased dynamics of the tail based on transition rates. Our study characterizes transition rates of all histone tails that can influence nucleosome plasticity and gene regulation.

biophysics↗

bioRxiv2024

Unveiling Nucleosome Dynamics: A Comparative Study Using All-Atom and Coarse-Grained Simulations Enhanced by Principal Component Analysis

This study investigates nucleosome dynamics using both all-atom and coarse-grained (CG) molecular dynamics simulations, focusing on the SIRAH force field. Simulations are performed for two nucleosomal DNA sequences--ASP and Widom-601--over six microseconds at physiological salt concentrations. Comparative analysis of structural parameters, such as groove widths and base pair geometries, reveals good agreement between atomistic and CG models, though CG simulations exhibit broader conformational sampling and greater breathing motion of DNA ends. Principal component analysis (PCA) is applied to DNA structural parameters, revealing multiple free energy minima, especially in CG simulations. These findings highlight the potential of the SIRAH CG force field for studying large-scale nucleosome dynamics, offering insights into DNA repositioning and sequence-dependent behavior.

biophysics↗