Structural and Dynamic Analysis on Disordered H4 Histone Tail by Modified AWSEM-MD

Abstract

DNA compaction in eukaryotic cells is mediated by positively charged octamers comprised of histone proteins. The latter consists of well folded core segments, that come together to form a central cylinder, and flexible tails, protruding out from cylinder's rim. Despite being disordered, histone tails play an important role in bridging interactions between neighboring nucleosomes, regulating folding structure and dynamics of chromatin fibers. Histone tails, in turn, are mainly regulated via post-translational modifications, such as methylation and acetylation at various positions. Because of their flexibility and disordered nature, it has been difficult to investigate histone tails both computationally and experimentally. In particular, it is desirable to develop coarse-grained, yet accurate models of histone tails, such that subsequent nucleosomal and polynucleosmal simulations could be carried out within feasible times. To achieve this goal, we added new interactions to the associative memory, water mediated, structure and energy model (AWSEM-MD), which is typically used for folding of globular proteins or binding studies. We found that modified AWSEM-MD reproduces well the complex conformational ensemble of the H4 histone tail, obtained from atomistic simulations with explicit solvent. In particular, the cumulative and site-specific effects of various acetylation combinations are consistent with the all-atom results. Our proposed extension of AWSEM-MD may allow simulating intrinsically disordered proteins with high accuracy and computational efficiency.