Free Energy Profiles for Nucleosomal DNA Unwrapping

Abstract

Eukaryotic genome is compactly stored into a tiny nucleus of cell in a form of protein-DNA complex. This protein-DNA complex is called as nucleosome which is composed of a histone octamer formed by two copies each of the four core histones H3, H4, H2A and H2B and about 150bp of DNA wrapping almost twice around the octamer. This compact form, however, has to be unwrapped in transcription, DNA duplication and DNA repair processes. To study the detailed molecular mechanism, we calculated free energy profiles for unwrapping nucleosomal DNA on H3-containg and CENP-A containing nucleosomes with adaptively biased MD and umbrella sampling. We estimated from the profiles that a cost for unwrapping the outer DNA is 0.1 to 0.4 kcal/mol/1bp, consistent with a value experimentally obtained. Compared with H3 nucleosome, the profile showed that CENP-A nucleosome was the most stable in a conformation where 15bp from each of ends were unwrapped. The detail analysis indicated that this is attributable to the difference in ability of forming hydrogen bond of αN helix of H3 and CENP-A. We unwrapped DNA further from the histone core up to 38bp from DNA ends. Relative distance matrix analysis showed that the distance between H2A-H2B and H3-H4 increased in a process of 0 to 17bp unwrapping. This distance decreased during a process of 17bp to 25bp unwrapping, indicating that the conformational relaxation occurred in the histone core.