Molecular dynamics simulations suggest novel allosteric modes in the Hsp70 chaperone protein

AbstractThe Hsp70 chaperone protein system is an essential component of the protein folding and homeostasis machinery in E.Coli. Hsp70 is a three domain, 70 kDa protein which functions as an allosteric system cycling between an ADP-bound state where the three domains are loosely coupled via a flexible interdomain linker and an ATP-bound state where they are tightly coupled into a single entity. The structure-function model of this protein proposes an allosteric connection between the 45 kDa Nucleotide Binding Domain (NBD) and the 25 kDa Substrate Binding Domain (SBD) and Lid Domain which operates through the inter NBD-SBD linker. X-Ray crystallography and NMR spectroscopy have provided structures of the end states of the functional cycle of this protein, bound to ADP and ATP. We have used MD simulations to study the transitions between these end states and allosteric communication in this system. Our results largely validate the experimentally derived allosteric model of function, but shed additional light on the flow of allosteric information in the SBD + Lid. Specifically, we find that the Lid domain has a double-hinged structure with the potential for greater conformational flexibility than was hitherto expected.Communicated by Ramaswamy H. SarmaKeywords: Chaperone proteinsmolecular dynamics simulationsallostery Author contributionsFM performed the simulations and carried out the analysis. The study was conceived by AB and SB. The paper was composed and edited by SB, AB.Disclosure statementThe authors confirm that there are no known conflicts of interest associated with this publication.Additional informationFundingSB acknowledges the HPC resources provided by the National Supercomputing Mission (DST/NSM/R&D_HPC Applications/2021/03.26), SERB MATRICS (MTR/2020/000334) and SERB grant CRG/2022/004108. Department of Science and Technology, Ministry of Science and Technology, India;Science and Engineering Research Board