Histone tails are highly flexible N terminal protrusions of histone proteins which help to fold DNA into dense superstructures known as chromatin. On a molecular scale histone tails are polyelectrolites with high degree of conformational disorder, allowing them to function as bio-molecular ”switches”, regulating various genetic regulatory processes via diverse types of covalent modifications. Because of being intrinsically disordered, the structural and dynamical aspects of histone tails are still poorly understood.
In this work we have investigated the impact of experimentally well studied covalent modification (acetylation of LYS-16) on conformational and DNA-binding propensities of H4 histone tail. We run long time REMD simulations on wild-type and covalently modified forms of H4 tails in presence of explicit water and ions. Our results demonstrated that introduction of acetyl group causes chain collapse and formation of alpha helical elements. To gain deeper understanding of the functional role of the H4 acetylation we studied the DNA binding of wild type (WT) and covalently modified histone tails via MD simulations. In particular we computed the potentials of mean force as a function of center of mass distance between model DNA and C terminal segment of WT and acetylated H4. Our results show that for WT H4 the binding free energy gain is sufficiently small (~2.5 kT) to set dynamic equilibrium between DNA-bound and unbound states, wheres WT is tightly bound to its own nucleosomal DNA ( ~ 5 kT). These findings lead us to propose a hypothesis that can potentially account for the chromatin “fiber loosening effects” observed in many experiments. Since the contribution of tail bridging between neighboring nucleosomes is found to be crucial for formation of dense chromatin fibers, acetylating H4 and inducing the collapsed alpha helical conformations will then significantly undermine the stability of chromatin fiber. This is simply because the acetylated tail prefers to bind its own nucleosomal DNA and is therefore deprived of the opportunity to mitigate the inter-nucleosomal electrostatic repulsion, which leads to local unfolding of chromatin fiber in the regions where H4 tail was acetylated.
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