SIN Mutations Alter Structure and Dynamics of Human Mononucleosomes

Abstract

ATP driven chromatin remodeling factors like SWI/SNF actively alter nucleosome structure and dynamics. Histone mutations have also been identified that alter nucleosome dynamics. These SIN (SWI/SNF INdependent) mutations alleviate transcriptional defects caused by the inactive SWI/SNF components. Crystal structures indicate alterations in local structure and stability, but the influence of these mutations on nucleosome dynamics and packing is not well understood. Here we analyze 1,020 ns of all atom molecular dynamics multiple replica simulation data of five SIN mutant mononucleosomes (H3-E105K, H3-R116H, H3-T118I, H4-V43I and H4-R45H) and a wild type human mononucleosome.Our simulations establish that SIN mutations influence the overall conformational state of nucleosomes, confer flexibility to the histone tails and alter the nucleosome core. Significant changes of N terminal tails of H3 and H2B as evidenced by RMS deviations are noted. The large fluctuations correlate with an increased mean radius of gyration in H3-R116H and H4-V43I. Hydrogen bond interaction profiles confirm changes in the nucleosome core packing. Analysis of the intra and extra base pair helical parameters indicate that SIN mutations induce significant differences in mean helical parameter values at SHLs ±0.5, ±3.5, ±4.5 and ±6.5, indicating that there exist multiple solutions for the path of the DNA superhelix at these locations. Each is an important site for association with SWI/SNF subunits. At SHLs (0, ±2.0, ±3.0) the path is clearly restricted. We have thus identified a multi-modal dynamic mechanism through which SIN mutants alter the behavior of the tails, as well as, the nucleosome core. Both affect the higher order structure of chromatin but through distinct mechanisms. Such mutations impact remodeling events during disease states and are being explored for functional roles in cancer.