Abstract
Centromere protein A (CENP-A) is a centromere-specific variant of histone H3 and shares almost 50% amino acid identity to canonical histone H3. CENP-A is required for packaging the centromere, to facilitate separation of sister chromatids during mitosis. Indeed, significant structural similarities have been reported to exist between CENP-A/H4 dimers and H3/H4 dimers in co-crystals. In this work, we used molecular dynamics simulations to map the binding free energy landscape for the CENP-A/H4 and H3/H4 dimers. The Associated memory, Water mediated, Structure and Energy Model (AWSEM) and umbrella sampling constraints were applied for each simulation system towards obtaining two-dimensional free energy profiles of monomeric protein association and folding. Surprisingly, our calculations revealed significant thermodynamic distinctions between dimerization profiles of CENP-A/H4 and of H3/H4 pairs. Furthermore, we also investigated the actions of various histones chaperones, finding that free energy landscapes of the CENP-A/H4 dimer is significantly remodeled in the presence of its cognate chaperone HJURP. The obtained results are in general agreement with the available experimental data and provide new thermodynamic insights into the mechanisms that form the basis of canonical and histone variant CENP-A nucleosomes assembly in vivo.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call