Molecular Simulations of the Structure/Function Relationship in Histone Variants

Illinois Institute Of Technology, Chicago IL

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Abstract

? DESCRIPTION (provided by applicant): Nature has evolved a hierarchy of mechanism to compact our genetic code while still making it accessible to the cellular machinery that controls gene expression and cell replication. The most basic unit of this process is the nucleosome core particle (NCP), an assembly of 147 base pairs of DNA that wraps around eight histone proteins. The long-term goal of this project is to advance our understanding of how the NCP functions and is regulated through a focus on its dynamical properties. To do this, we will employ state of the art computational methods to simulate the movement of each individual atom in the system. Work will be performed in collaboration with experimentalists that utilize the techniques of small angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy. This proposal describes the first steps towards this goal. Specifically, we will be focusing on understanding the dynamics of the standard and several variant NCPs. These variants contain proteins with different primary sequences then the standard histones, and that have been shown to alter the number of DNA basepairs wrapped around the histone core and the stability of the NCP as a whole. Simulation work will be divided into two phases. In the first phase, we will use standard and enhanced sampling molecular dynamics simulations to simulate the standard NCP, along with NCPs containing two variants of the histone H2A. Analysis will focus on large-scale conformational transitions, the stability of DNA-protein and protein-protein contacts, and allosteric networks throughout the complex. In the second phase, we will perform biased simulations that will help us interpret low-resolution data from SAXS experiments in the context of high-resolution NCP structures. This work will also be performed for two variant containing NCPs. Overall, results from both phases will advance our understanding of the link between function and dynamics in the nucleosome, and how the cell regulates these processes to control gene expression.