Abstract
Histone chaperones facilitate assembly and disassembly of nucleosomes. Understanding the process of how histone chaperones associate and dissociate from the histones can help clarify their roles in chromosome metabolism. Some histone chaperones are intrinsically disordered proteins (IDPs). Recent studies of IDPs revealed that the recognition of the biomolecules is realized by the flexibility and dynamics, challenging the century-old structure-function paradigm. Here we investigate the binding between intrinsically disordered chaperone Chz1 and histone variant H2A.Z-H2B by developing a structure-based coarse-grained model, in which Debye-Hückel model is implemented for describing electrostatic interactions due to highly charged characteristic of Chz1 and H2A.Z-H2B. We find that major structural changes of Chz1 only occur after the rate-limiting electrostatic dominant transition state and Chz1 undergoes folding coupled binding through two parallel pathways. Interestingly, although the electrostatic interactions stabilize bound complex and facilitate the recognition at first stage, the rate for formation of the complex is not always accelerated due to slow escape of conformations with non-native electrostatic interactions at low salt concentrations. Our studies provide an ionic-strength-controlled binding/folding mechanism, leading to a cooperative mechanism of “local collapse or trapping” and “fly-casting” together and a new understanding of the roles of electrostatic interactions in IDPs' binding.
Highlights
Nucleosome, the fundamental repeating structural unit of chromatin, is comprised of two superhelical turns of DNA (*146 base pairs) wound *1:7 times around an octamer of histone proteins (H2A, H2B, H3, H4) or their variants [1,2,3,4]
The experiments have explored that the histone chaperon Chz1 as an intrinsically disordered protein (IDP) can fold by binding to its histone variants H2A.Z-H2B
We developed a molecular simulation program that treated electrostatic interactions with Debye-Huckel model to study the mechanism of the association
Summary
Nucleosome, the fundamental repeating structural unit of chromatin, is comprised of two superhelical turns of DNA (*146 base pairs) wound *1:7 times around an octamer of histone proteins (H2A, H2B, H3, H4) or their variants [1,2,3,4]. The histone proteins are highly positively charged and usually associated with their binding partners, such as DNA and histone chaperones, through electrostatic interactions [12]. Because of the oppositely charged characteristic between histone chaperones and histones, the electrostatic interactions rather than hydrophobic interactions are supposed to highly participate in these molecular events. Some histone chaperones are intrinsically disordered proteins (IDPs) [9], indicating that the association and dissociation are coupled with folding and unfolding of polypeptide chains. The studies of IDPs have put forward a new dynamics-function paradigm for biomolecular recognition [13,14]
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