Abstract
The intrinsically disordered, positively charged H4 histone tail is important for chromatin structure and function. We have explored conformational ensembles of human H4 tail in solution, with varying levels of charge neutralization via acetylation or amino-acid substitutions such as K→Q. We have employed an explicit water model shown recently to be well suited for simulations of intrinsically disordered proteins. Upon progressive neutralization of the H4, its radius of gyration decreases linearly with the tail charge q, the trend is explained using a simple polymer model. While the wild type state (q=+8) is essentially a random coil, hyper-acetylated H4 (q=+3) is virtually as compact and stable as a globular protein of the same number of amino-acids. Conformational ensembles of acetylated H4 match the corresponding K→X substitutions only approximately: based on the ensemble similarity, we propose K→M as a possible alternative to the commonly used K→Q. Possible effects of the H4 tail compaction on chromatin structure are discussed within a qualitative model in which the chromatin is highly heterogeneous, easily inter-converting between various structural forms. We predict that upon progressive charge neutralization of the H4 tail, the least compact sub-states of chromatin de-condense first, followed by de-condensation of more compact structures, e.g. those that harbor a high fraction of stacked di-nucleosomes. The predicted hierarchy of DNA accessibility increase upon progressive acetylation of H4 might be utilized by the cell for selective DNA accessibility control.