Insights into the molecular mechanism underlying CD4-dependency and neutralization sensitivity of HIV-1: a comparative molecular dynamics study on gp120s from isolates with different phenotypes

Abstract

The envelope (Env) of HIV-1 plays critical roles in viral infection and immune evasion.

Probing intrinsic dynamics and conformational transition of HIV gp120 by molecular dynamics simulation

“…Our previous simulation studies on gp120 from two extreme neutralization phenotype HIV strains also revealed the effect of mutations on structural dynamics. 29 Our team is preparing a study on more in-depth molecular dynamics of gp120 from different HIV-1 isolates. Like the case study about NPAC, 30 a cytokine-like nuclear factor involved in chromatin modication and regulation of gene expression, we expect to identify key mutations that affect the conformational exibility of gp120 in future studies.…”

Molecular dynamics simulations reveal distinct differences in conformational dynamics and thermodynamics between the unliganded and CD4-bound states of HIV-1 gp120

“…Note that for the unliganded and CD4-complexed gp120s, the first two eigenvectors cumulatively contribute 40.5% and 51.8% to TMSF, respectively. Our previous work 28,32,33 and other studies 26,34 have shown that the first few eigenvector projections are good reaction coordinates capable of distinguishing among different conformational states/substates sampled by MD simulations; furthermore, the evaluation of conformational sampling with cosine contents of the first few eigenvectors indicates that our ms-scale multiplereplica MD simulations have achieved a sufficient convergence of the conformational sampling. Therefore, our constructed FELs are accurate enough to provide reliable information on the thermodynamics and kinetics of the two forms of gp120 near their starting states.…”

“…6A). 25,32 In such a stable ground state, the vulnerable epitopes recognized by the highly potent neutralizing antibodies are buried, whereas the immunodominant epitopes recognized by the non-neutralizing or less potent antibodies are exposed. 16,44,45 Therefore, before viral infection, the stable maintenance of gp120 close to the unliganded state provides a thermodynamic basis for HIV-1 neutralization resistance.…”

“…5D), the twisting of V1/V2 will result in the departure of the loop V1 from while the approach of L1 to the core; and (iv) the contraction, twisting, elongation, or widening of the entire structure/hydrophobic cavity arising from the collective motions of the unliganded gp120 may either contribute to maintaining the unliganded state or be conducive to the initial association with CD4 or even initiating the spontaneous transition to the CD4-bound state. 32 Upon CD4 binding, the gp120 structure becomes unstable, exhibiting increased flexibility, more diversified motion modes, and more complicated thermodynamic and kinetic behaviors compared to that before CD4 binding. This seems to be a double-edged sword regarding the gp120 functions.…”

Insights into the role of electrostatics in temperature adaptation: a comparative study of psychrophilic, mesophilic, and thermophilic subtilisin-like serine proteases

“…Each system was subjected to 1000 steps of steepest-descent energy minimization followed by 1000 steps of conjugate-gradient minimization. The last minimization was followed by four successive 100 ps position-restrained MD simulations in the isochoric-isothermal (NVT) ensemble, with protein heavy atoms and Ca 2+ restrained by the harmonic potential with reduced force constants (i.e., Kposres ¼ 1000, 100, 10, and 0 kJ mol À1 nm À2 ) 38,40 and temperature maintained at 300 K using a velocity rescaling thermostat. 41 Finally, at each of the three temperatures (i.e., 283, 300, and 343 K, which are the approximate habitat temperatures of the source organisms of VPR, PRK, and AQN, respectively), ve 30 ns production MD runs were performed in the NPT ensemble.…”