Electrostatic and structural mechanisms of chromatin folding regulation by histone tail posttranslational modifications
DNA folds into a highly organized chromatin structure in the eukaryotic cells by associating with histone protein octamers. It is hypothesized that histone-tail post-translational modifications directly regulate chromatin higher-order folding, determining the extent of accessibility of specific DNA sequences. This, in turn, controls important DNA- templated processes, such as gene expression, recombination, and repair. Consequently, chromatin misregulation may result in developmental defects and cancer in eukaryotic organisms, including humans. How histone-tail post- translational modifications modulate chromatin conformational dynamics is poorly understood. All-atom Molecular Dynamics (MD) simulations could provide crucial insights into the electrostatic and structural mechanisms of chromatin folding. However, because of enormous size of even short chromatin fiber segments and long folding time-scales, using all-atom MD simulations will be computationally impractical in the foreseeable future. Alternative computational approaches, based on the continuum electrostatics approximation and drastically simplified representations of chromatin fiber structure, have been used. However, our all-atom explicit solvent MD investigation of ionic atmosphere around a 16 base pair DNA oligomer has indicated that major qualitative and quantitative differences exist between the more exact MD simulations and the predictions from the continuum electrostatics calculations, especially in the proximity of the DNA surface. During proposed research, we will build accurate coarse-grained computational models for polynucleosomal arrays, derived systematically from all-atom MD simulations, instead of relying only on interactions derived from continuum electrostatics. This approach will allow investigation of chromatin conformational dynamics at much higher resolution than earlier studies. In particular, we will examine the effect of histone tail acetylation on higher-order chromatin folding. We will focus our efforts on individual acetylation sites that are known to be important, such as K8 and K16 in histone H4, and elucidate the effects of hyper-acetylation. We will validate and improve our computational models by comparing our predictions with the experimental results.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.