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Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120

Although the crystal structures of the HIV-1 gp120 core bound and pre-bound by CD4 are known, the details of dynamics involved in conformational equilibrium and transition in relation to gp120 function have remained elusive. The homology models of gp120 comprising the N- and C-termini and loops V3 a...

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Autores principales: Sang, Peng, Yang, Li-Quan, Ji, Xing-Lai, Fu, Yun-Xin, Liu, Shu-Qun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126740/
https://www.ncbi.nlm.nih.gov/pubmed/25105502
http://dx.doi.org/10.1371/journal.pone.0104714
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author Sang, Peng
Yang, Li-Quan
Ji, Xing-Lai
Fu, Yun-Xin
Liu, Shu-Qun
author_facet Sang, Peng
Yang, Li-Quan
Ji, Xing-Lai
Fu, Yun-Xin
Liu, Shu-Qun
author_sort Sang, Peng
collection PubMed
description Although the crystal structures of the HIV-1 gp120 core bound and pre-bound by CD4 are known, the details of dynamics involved in conformational equilibrium and transition in relation to gp120 function have remained elusive. The homology models of gp120 comprising the N- and C-termini and loops V3 and V4 in the CD4-bound and CD4-unbound states were built and subjected to molecular dynamics (MD) simulations to investigate the differences in dynamic properties and molecular motions between them. The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations. For both the unbound and bound gp120, the large concerted motions derived from essential dynamics (ED) analyses can influence the size/shape of the ligand-binding channel/cavity of gp120 and, therefore, were related to its functional properties. The differences in motion direction between certain structural components of these two forms of gp120 were related to the conformational interconversion between them. The free energy calculations based on the metadynamics simulations reveal a more rugged and complex free energy landscape (FEL) for the unbound than for the bound gp120, implying that gp120 has a richer conformational diversity in the unbound form. The estimated free energy difference of ∼−6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability “ground state” for gp120 and explaining why the unbound state resists crystallization. Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.
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spelling pubmed-41267402014-08-12 Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120 Sang, Peng Yang, Li-Quan Ji, Xing-Lai Fu, Yun-Xin Liu, Shu-Qun PLoS One Research Article Although the crystal structures of the HIV-1 gp120 core bound and pre-bound by CD4 are known, the details of dynamics involved in conformational equilibrium and transition in relation to gp120 function have remained elusive. The homology models of gp120 comprising the N- and C-termini and loops V3 and V4 in the CD4-bound and CD4-unbound states were built and subjected to molecular dynamics (MD) simulations to investigate the differences in dynamic properties and molecular motions between them. The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations. For both the unbound and bound gp120, the large concerted motions derived from essential dynamics (ED) analyses can influence the size/shape of the ligand-binding channel/cavity of gp120 and, therefore, were related to its functional properties. The differences in motion direction between certain structural components of these two forms of gp120 were related to the conformational interconversion between them. The free energy calculations based on the metadynamics simulations reveal a more rugged and complex free energy landscape (FEL) for the unbound than for the bound gp120, implying that gp120 has a richer conformational diversity in the unbound form. The estimated free energy difference of ∼−6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability “ground state” for gp120 and explaining why the unbound state resists crystallization. Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120. Public Library of Science 2014-08-08 /pmc/articles/PMC4126740/ /pubmed/25105502 http://dx.doi.org/10.1371/journal.pone.0104714 Text en © 2014 Sang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sang, Peng
Yang, Li-Quan
Ji, Xing-Lai
Fu, Yun-Xin
Liu, Shu-Qun
Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120
title Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120
title_full Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120
title_fullStr Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120
title_full_unstemmed Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120
title_short Insight Derived from Molecular Dynamics Simulations into Molecular Motions, Thermodynamics and Kinetics of HIV-1 gp120
title_sort insight derived from molecular dynamics simulations into molecular motions, thermodynamics and kinetics of hiv-1 gp120
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126740/
https://www.ncbi.nlm.nih.gov/pubmed/25105502
http://dx.doi.org/10.1371/journal.pone.0104714
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