Multiscale Simulations Of Nucleosome Stability Affected By Histone Variant H2A.B

As the basic constituent unit of chromatin,the structural composition and dynamic changes of nucleosome play a significant role in the life activities of cells.There are several ways to regulate the structure of nucleosomes or chromatin that related to gene activity in cells,such as histone posttranslational modifications,and histone variants.Histone variants are usually found in H3 and H2A histone family,nucleosomes containing histone variants often have different structural features and functional properties compared with conventional nucleosomes.H2A.B is a variant of histone H2A,which is associated with transcriptionally active genes,that is,H2A.B nucleosomes can facilitate gene transcription.The structure of nucleosomes containing H2A.B is highly dynamic which was confirmed by previous study by using biochemistry and biophysics methods,and the ends of DNA in H2A.B nucleosomes are easily dissociated from the histone octamer.The high-resolution three-dimensional structure of H2A.B nucleosomes has not to date been obtained by traditional experiments due to its high dynamic attribute.Therefore,molecular mechanism of the specific properties of H2A.B nucleosomes remains to be elucidated.Besides some experimental methods,in recent years,with the development of bioinformatics,computer science,and multidisciplinary integration,the computer simulation technology of biomacromolecules has become more and more important in the field of life sciences.Multiscale simulation is also an essential method for studying the structure and conformational changes of biomacromolecules.All-atom molecular dynamics(MD)simulation is accurate and can provide detailed information at the atom level of biomacromolecules.However,all-atom MD simulation is a computationally expensive method,thereby limiting time scale of all-atom MD simulations.Because coarse-grained simulation simplifies the structural model and loses some detailed information,it can reduce the amount of computation cost.Therefore,coarse-grained simulation can simulate larger molecules for a longer time scale,and thus obtaining much more conformational changes of biomacromolecules.In order to apply computer simulation techniques to study the specific properties of H2A.B nucleosomes and its related molecular mechanisms,multiscale simulations were performed in this study.We initially built the full-length atomic structure model of conventional nucleosomes and H2A.B nucleosomes,and then the all-atom molecular dynamics simulations and coarse-grained simulations were also used to make sufficient multiscale simulations for conventional nucleosome,H2A.B nucleosome and mutant nucleosome systems.Based on simulated trajectories,we observed the conformational changes consistent with the experimental results of H2A.B nucleosomes and other nucleosome-related systems,and then proposed relevant molecular mechanisms for the specific properties of H2A.B nucleosomes through analysis and validation of simulation data.