One copy of three million base pairs in the genome can reach a length of over two meters in the fully extended state. Yet, it must be packaged into a eukaryotic cell of a diameter of only 10 micrometers. This is achieved by the formation of chromatin, a polymeric complex of an elementary repeating unit called a nucleosome. The nucleosome core particle (NCP) consists of 145-147 base duplex DNA wrapped around an octameric histone protein. Disassembly and reassembly of the nucleosomal DNA are associated with various DNA metabolic processes. Therefore, understanding the conformational dynamics of the nucleosome is central to unravel such DNA metabolic processes. Herein we perform 12-microsecond long molecular dynamics simulations of two nucleosomes with varying DNA sequences at high salt concentration. We compare how the alpha-satellite palindromic (ASP) nucleosomal DNA sequence and the Widom-601 sequence impact the structure and stability of the nucleosome. We characterize how the variation of DNA sequence impacts nucleosome conformation. Key histone residues responsible for controlling the overall conformational dynamics of the nucleosome are identified; a correlation of these residues with the observed difference in the conformations between the two nucleosomes. These key residues exhibit high positive self-conditional activity, a timing correlation function recently introduced in the literature calculated from the time series of transitions of sidechains among uniquely defined rotamers. Our results provide insight into the critical sequence-dependent barriers to nucleosome unwrapping.

Role of DNA sequence on the conformational dynamics of the nucleosome from molecular dynamics simulations

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.