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

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...

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Autores principales: Yu, Alvin, Lee, Elizabeth M. Y., Jin, Jaehyeok, Voth, Gregory A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494349/
https://www.ncbi.nlm.nih.gov/pubmed/32938668
http://dx.doi.org/10.1126/sciadv.abc6465
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author Yu, Alvin
Lee, Elizabeth M. Y.
Jin, Jaehyeok
Voth, Gregory A.
author_facet Yu, Alvin
Lee, Elizabeth M. Y.
Jin, Jaehyeok
Voth, Gregory A.
author_sort Yu, Alvin
collection PubMed
description 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.
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spelling pubmed-74943492020-09-23 Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP(6)) Yu, Alvin Lee, Elizabeth M. Y. Jin, Jaehyeok Voth, Gregory A. Sci Adv Research Articles 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. American Association for the Advancement of Science 2020-09-16 /pmc/articles/PMC7494349/ /pubmed/32938668 http://dx.doi.org/10.1126/sciadv.abc6465 Text en 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). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Yu, Alvin
Lee, Elizabeth M. Y.
Jin, Jaehyeok
Voth, Gregory A.
Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP(6))
title Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP(6))
title_full Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP(6))
title_fullStr Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP(6))
title_full_unstemmed Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP(6))
title_short Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP(6))
title_sort atomic-scale characterization of mature hiv-1 capsid stabilization by inositol hexakisphosphate (ip(6))
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494349/
https://www.ncbi.nlm.nih.gov/pubmed/32938668
http://dx.doi.org/10.1126/sciadv.abc6465
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