title: Insight derived from molecular dynamics simulations into molecular motions, thermodynamics and kinetics of HIV-1 gp120.
abstract: 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.
authors.affiliation: Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sang
authors.affiliation: Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, P.R. China; College of Agriculture and Biological Science, Dali University, Dali, P.R. China.
authors.forename: Li-Quan
authors.initials: LQ
authors.lastname: Yang
authors.affiliation: Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, P.R. China; Southwest Biological Diversity Laboratory, Kunming Branch of Chinese Academy of Sciences, Kunming, P.R. China; Key Laboratory for Animal Genetic Diversity and Evolution of High Education in Yunnan Province, Kunming, Yunnan University, Kunming, P.R. China.
authors.forename: Xing-Lai
authors.initials: XL
authors.lastname: Ji
authors.affiliation: Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, P.R. China; Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, United States of America.
authors.forename: Yun-Xin
authors.initials: YX
authors.lastname: Fu
authors.affiliation: Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, P.R. China; Southwest Biological Diversity Laboratory, Kunming Branch of Chinese Academy of Sciences, Kunming, P.R. China; Key Laboratory for Animal Genetic Diversity and Evolution of High Education in Yunnan Province, Kunming, Yunnan University, Kunming, P.R. China.
authors.forename: Shu-Qun
authors.initials: SQ
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016415:Sequence Alignment; D013816:Thermodynamics
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120
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