Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP 6 ).

Autor: Yu A; Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL 60637, USA., Lee EMY; Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA., Jin J; Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL 60637, USA., Voth GA; Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL 60637, USA. gavoth@uchicago.edu.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2020 Sep 16; Vol. 6 (38). Date of Electronic Publication: 2020 Sep 16 (Print Publication: 2020).
DOI: 10.1126/sciadv.abc6465
Abstrakt: Inositol hexakisphosphates (IP 6 ) are cellular cofactors that promote the assembly of mature capsids of HIV. These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP 6 increases the stable lifetimes of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP 6 We find that capsid hexamers and pentamers have differential binding modes for IP 6 Ligand density calculations show three sites of interaction with IP 6 including at a known capsid inhibitor binding pocket. Free energy calculations demonstrate that IP 6 preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly. These results elucidate the molecular role of IP 6 in stabilizing and assembling the retroviral capsid.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze: MEDLINE
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