Dissertations, Theses, and Capstone Projects

Date of Degree

6-2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biochemistry

Advisor

Sharon Loverde

Committee Members

Tom Kurtzman

Mariana Torrente

Sébastien Poget

Glen Hocky

Subject Categories

Biophysics | Other Biochemistry, Biophysics, and Structural Biology

Keywords

NCP, H2BE76K, H4R92T, MM/GBSA, ANTON2, MD Simulation

Abstract

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. How DNA communicates with histones, and how this information propagates through the histone, has been suggested to be a cooperative process. Here, I investigate the molecular consequences of two mutations, H2BE76K and H4R92T, using 36 µs of all-atom molecular dynamics simulations on Anton2. I also characterize the kinetic correlation within histone/DNA domains via conditional activity (CONDACT) using the dihedral angle as our degrees of freedom. I showed that these mutations destabilize the H2B-H4 interface by disrupting critical salt bridges and hydrogen bonds, thereby reducing the binding free energy at this interface. Principal component analysis reveals altered helix conformations and increased interhelical distances in mutant systems. I found correlated domains in histone and double-stranded DNA, with some kinetically correlated residues exhibiting high dynamical memory up to 7.5 nm apart. This work provides insight into how these mutations compromise nucleosome stability and kinetically communicate this destabilization throughout the tetramer-dimer interface, which could help propose mechanisms to enhance chromatin accessibility and address gene dysregulation in cancer.

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