| Summary: | The recruitment and transference of proteins through protein−protein interactions is a general process involved in various biological functions in cells. Despite the importance of this general process, the dynamic mechanism of how proteins are recruited and transferred from one interacting partner to another remains unclear. In this study, we investigated the dynamic mechanisms of recruitment and translocation of histone chaperone CIA/ASF1 for nucleosome disassembly by exploring the conformational space and the free energy profile of unbound DBD(CCG1) and CIA/ASF1-bound DBD(CCG1) systems through extensive molecular dynamics simulations. It was found that there exists three metastable conformational states for DBD(CCG1), an unbound closed state, a CIA/ASF1-bound half-open state, and an open state. The free energy landscape shows that the closed state and the half-open state are separated by a high free energy barrier, while the half-open state and the open state are connected with a moderate free energy increase. The high free energy barrier between the closed and half-open states explains why DBD(CCG1) can recruit CIA/ASF1 and remain in the binding state during the transportation. In addition, the asymmetric binding of CIA/ASF1 on DBD(CCG1) allows DBD(CCG1) to adopt the open state by moving one of its two domains, such that the exposed domain of DBD(CCG1) is able to recognize the acetylated histone H4 tails. As such, CIA/ASF1 has a chance to translocate from DBD(CCG1) to histone, which is also facilitated by the moderate energy increase from the bound half-open state to the open state of DBD(CCG1). These findings suggest that the recruitment and transference of histone chaperone CIA/ASF1 is highly favored by its interaction with DBD(CCG1) via conformational selection and asymmetric binding, which may represent a general mechanism of similar biological processes.
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