Chemical modifications on histones, collectively called the histone code, are involved in regulation of gene expression, cell cycle and genome stability. The grand structural challenge of the histone code is that full-length effector proteins, whose function is to �read� and transmit the �encoded� information, are too large and flexible for crystallization studies and NMR. The computational models and simulations can step in and bridge the gap between the macro- and microscopic scales and provide a space- and time-resolved picture. For instance, we recently demonstrated how a simple model based upon the statistical mechanics formalism can quantitatively describe the energetics of multivalent effector-chromatin binding. Application of this model revealed an intriguing mechanism (that we refer to as �entropic lock and key�) of how the effectors find their respective sites and resolved the existing multivalent-free-energy conundrum. Furthermore, all-atom metadynamics helped to understand the structural detail of the multivalent chromatin engagement, expose the significance of intrinsically disordered linkers and rationalize the function of the histone-code effectors. This work has inspired new biochemical, biophysical and cell-based experiments that corroborated our theoretical and computational findings. Several studies involving therapeutically important multi-domain effectors � UHRF1, BPTF and CHD4 � will be reviewed.

Entropic keys to the histone code

247th National Meeting (2014)

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