Comparative Molecular Dynamics Simulations Of The Unliganded And The Liganded HIV-1 Gp120s

HIV-1,which is a RNA retroviruse,can infect human host cells mediated through its outer membrane glyco-protein gp120.Although there have been many reports about the dynamic behaviors of gp120,these studies were based on the crystallographic core structure of gp120.Since the core structure of gp120 lacks functionally important loop regions,especially the V1/V2 loop,such studies are insufficient to fully reflect the structure-dynamics-function relationship of gp120.In this paper,using the near-full-length gp120 structures extracted from the closed and open HIV-1 envelope trimers as templates,we built structural models of relatively complete gp120 in the unliganded state and gp120-CD4 complex in which gp120 is in the liganded state,respectively.Subsequently,these two models were subjected to molecular dynamics simulations followed by a series of analyses to probe the differences in dynamic properties,the motion modes,the conformational sampling,and the free energy landscapes between the liganded gp120 and unliganded gp 120.The results of comparative analysis of geometric/structural properties reveal that the unliganded gp120 adopts a more compact and stable conformation than the liganded gp120.Calculations and comparison of the RMSF(root mean square fluctuation)values reveal that the liganded gp 120 has a higher global conformational flexibility than the unliganded gp120;this is possibly due to the separation of V1/V2 loop from V3 loop in the liganded gp120 upon CD4 binding,thus relaxing the conformational constraints imposed on V1/V2 and V3 and eventually causing an increase in their conformational flexibility.It should be noted that the exposure of V3 loop,and hence its increased flexibility,could promote the binding of gp120 to the coreceptor.The results of essential dynamics analysis indicate that the motion modes of these two gp120s mainly exhibit as vortex-like rotation or translation involving either the global structure or local structural regions,which would lead to torsion,expansion,contraction,separation,or proximity of relevant structural regions and,therefore,these motion modes may be related to the functional roles of gp120 and the conversion between different conformational states of gp120.The result of comparative analyses of combined essential dynamics,conformational space sampling,and free energy landscapes collectively indicate that,when compared to the unliganded gp120,liganded gp120 has a stronger conformation-changing ability,more conformational sub-states(or greater conformational entropy),and more unstable structure,synthesising the above results,we speculate that the unliganded state was the stable state(or ground state)of gp120.Although the human immune system would produce antibodies against such a ground state,higher conformational flexibility and stronger conformation-changing capacity of the liganded gp120 upon CD4 binding make it impossible for the ground state-directed antibodies to neutralize the gp120-CD4 complex.On the other hand,the conformational diversity of the liganded gp120 can facilitate(or perturb)its interactions with other functional receptors(such as CCR5)and subunits(such as gp41),and therefore is beneficial to HIV-1 invasion.Our study elucidates the differences in structural dynamics,molecular motions,and free energy landscapes between the unliganded gp120 and the liganded gp120,and facilitates the understanding of HIV-1 infection mechanism and immune escape mechanism.