Biology subjects

Ghosh Moulick, A.

Publications and source records attributed to Ghosh Moulick, A..

3 recordsLinked to original sources

bioRxiv2026

DNA Sequence Differentially Modulates Histone Core and Tail Interactions in Canonical and Centromeric Nucleosomes

Human centromeric chromatin is a specialized chromatin domain characterized by CENP-A-containing nucleosomes interspersed with canonical histone H3 nucleosomes. It is assembled on tandem repeats of -satellite DNA and defines centromere identity. How histone variant identity and DNA sequence jointly shape nucleosome structure and histone-DNA interactions that underpin centromeric chromatin formation remains incompletely understood. Here, we investigate the structural plasticity of the histone core and nucleosomal DNA, histone tail dynamics and DNA-sequence dependent changes for canonical (H3) and centromeric (CENP-A) nucleosomes using the SIRAH coarse-grained molecular dynamics (CG-MD) simulations. Nucleosomes containing -satellite positioning sequence (ASP) and Widom 601 DNA sequence are systematically analyzed and compared. Our simulations reveal that the centromeric nucleosome exhibits a more stable histone core with lower structural plasticity and the histone tails engage DNA differently with an overall reduction in the histone-DNA contacts compared to the canonical nucleosome. Further investigation of CENP-N binding to the CENP-A nucleosome demonstrates substantial modulation of nucleosomal DNA dynamics and histone-DNA interactions. Replacing the ASP DNA sequence with the Widom 601 sequence preserves the stability of both types of the histone core while markedly altering histone-tail dynamics. The conformational dynamics of canonical nucleosomes is more strongly affected by the Widom 601 DNA sequence than those of their centromeric counterparts. However, CENP-N binding induces more spatially extensive changes in DNA geometry in Widom 601 than in ASP DNA. Our findings suggest that DNA sequence and histone composition have residue-level differences translating into distinct nucleosome dynamics, which could be among the determinants governing the structural and dynamic properties of centromeric chromatin and its biological function.

biophysics↗

bioRxiv2025

Structural dynamics in the CENP-A nucleosome impacted by protein-protein interactions with centromere protein N

Noncanonical nucleosomes at the centromere contain the histone variant CENP-A, playing a crucial role in chromosome segregation. CENP-A is highly regulated and its centromeric organization is partially regulated by the centromere protein N (CENP-N). Despite its importance, the protein-protein interactions within the complex formed between CENP-A nucleosomes and CENP-N remain poorly understood at a molecular level. Here, we employ the SIRAH coarse-grained molecular dynamics (MD) simulations to investigate the binding interface and structural rearrangements of proteins in the CENP-A nucleosome complexed with CENP-N. We aim to assess the stability of the CENP-A nucleosome and the change in its plasticity upon the CENP-N binding. By the set of {micro}s-long MDs, we reveal enhanced flexibility in the N-terminal region of CENP-A and stabilization of its RG loop in the complex with CENP-N. This is demonstrated to have rather minor effects on the overall stability of the nucleosome and changing its compactness. Nevertheless, the data suggest the binding of CENP-N allosterically changes the conformational states of CENP-A and impacts its interactions with other proteins in the histone core. A distance-based contact map analysis further elucidates key residues mediating the interaction between CENP-A and CENP-N, while umbrella sampling simulations quantify their binding free energy, which remains challenging to measure experimentally.

biophysics↗

bioRxiv2021

Correlated dipolar and dihedral fluctuations in a protein

Correlation between dihedral fluctuations is a possible way to understand coordination between various amino acid residues of the protein. The nanosecond timescales of correlated fluctuations of dihedral angle do not allow direct probing by experimental methods. However, NMR experiments probe dipolar fluctuations given in terms of cross correlated relaxation (CCR) rates, expressed as zero frequency spectral density function (J) of the fluctuations of the mutual orientation of two spatially separated dipole vectors. Here we illustrate the correlation of protein dipolar and dihedral angle using molecular dynamics simulation of protein Ubiquitin (Ub) and GB3. We calculate CCR rates between protein bond vector from simulation and compare with CCR data obtained from NMR experiments. A good correlation between theoretical and experimental values is found. We further show that the zero frequency spectral functions of backbone dihedral{psi} auto-correlation function and dipole orientation fluctuations show strong correlations. These correlations are not sensitive to protein and forcefield parameters. Hence, CCR may act as a marker for protein backbone dihedral fluctuations.

biophysics↗