# Computational Methods to Characterize Structure and Dynamics of the Nucleosome Core Particle

> **NIH NIH R15** · COLLEGE OF STATEN ISLAND · 2022 · $494,386

## Abstract

The nucleosome core particle (NCP) is the basic building block of chromatin, which is a compact, yet
dynamic structure that packages DNA. The NCP consists of a positively charged histone octameric core,
surrounded by negatively charged nucleosomal DNA which is wrapped ~ 1.7 times around the core. There are
many levels of structure in chromatin organization, ranging from the packaging of DNA around the NCP to
compact chromatin fibers with diameters ~ 30 nm to denser chromatin fibers in metaphase chromosome with
diameters ~ 1.5 µm. DNA binding proteins such as transcription factors and chromatin remodelers need to bind
nucleosomal DNA. Thus, in order for transcription to occur, the nucleosomal DNA needs to unwrap fully or
partially from the histone core. Modification of the histone core, commonly known as post-translational
modification (PTM), can allow for easier access to nucleosomal DNA through modifications in the structure and
dynamics of the NCP. Covalent modifications of either histone proteins or DNA often control gene activity and
they are the most important epigenetic markers. Furthermore, mutations in chromatin components, such as
the NCP, are also found to be commonly involved in diseases such as cancer. The innovative aspect of this
proposal is the development of free energy methods in molecular dynamics to characterize complex reaction
coordinates in hierarchical protein-nucleic acid assemblies. The PI will develop new computational
methods/reaction coordinates to be used in free energy methods, validate atomistic force fields with local
collaborators, and develop further methods to predict the impact of single amino acid mutations on nucleosome
stability. We expect that the results from these computational investigations can add additional insight into the
rational design of experimental investigations into fundamental chromatin structure. The PI’s laboratory will
utilize advanced sampling methods in molecular dynamics to characterize the stability of the nucleosome core
particle. The role of nucleic acid sequence, PTM, and oncogenic mutations on stability will be elucidated.
Force fields for histone tails will be validated through comparison with NMR studies with local collaborators.
New methodology to predict the effect of oncogenic mutations on NCP stability will be developed. Results will
be tested by collaborators at MSKCC. The computational force fields and methodologies developed during the
course of this proposed work could be used to characterize the interactions of nucleic acids and proteins in
other macromolecular assemblies, for example, viruses

## Key facts

- **NIH application ID:** 10442803
- **Project number:** 1R15GM146228-01
- **Recipient organization:** COLLEGE OF STATEN ISLAND
- **Principal Investigator:** Sharon Marie Loverde
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $494,386
- **Award type:** 1
- **Project period:** 2022-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442803

## Citation

> US National Institutes of Health, RePORTER application 10442803, Computational Methods to Characterize Structure and Dynamics of the Nucleosome Core Particle (1R15GM146228-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10442803. Licensed CC0.

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