Abstract
To understand the underlying mechanisms of significant differences in dissociation rate constant among different inhibitors for HIV-1 protease, we performed steered molecular dynamics (SMD) simulations to analyze the entire dissociation processes of inhibitors from the binding pocket of protease at atomistic details. We found that the strength of hydrogen bond network between inhibitor and the protease takes crucial roles in the dissociation process. We showed that the hydrogen bond network in the cyclic urea inhibitors AHA001/XK263 is less stable than that of the approved inhibitor ABT538 because of their large differences in the structures of the networks. In the cyclic urea inhibitor bound complex, the hydrogen bonds often distribute at the flap tips and the active site. In contrast, there are additional accessorial hydrogen bonds formed at the lateral sides of the flaps and the active site in the ABT538 bound complex, which take crucial roles in stabilizing the hydrogen bond network. In addition, the water molecule W301 also plays important roles in stabilizing the hydrogen bond network through its flexible movement by acting as a collision buffer and helping the rebinding of hydrogen bonds at the flap tips. Because of its high stability, the hydrogen bond network of ABT538 complex can work together with the hydrophobic clusters to resist the dissociation, resulting in much lower dissociation rate constant than those of cyclic urea inhibitor complexes. This study may provide useful guidelines for design of novel potent inhibitors with optimized interactions.
Highlights
Human immunodeficiency virus type 1 (HIV-1) protease is a symmetric homo-dimeric aspartyl protease, which cleaves the gag and pol viral polyproteins at its active site to process viral maturation [1]
The catalytic Asp side chains of the bound complex were protonated according to the experiments and theoretical calculations, i.e. both side chains of Asp25/Asp259 were protonated for AHA001 and XK263 bound complex [35], and only one of the Asp25/Asp259 was protonated for ABT538 bound complex [36]
We showed that the dissociation processes of these three inhibitors were different in several aspects including, e.g., the dissociation time, rupture force, and the failure modes of hydrogen bond (H-bond) and hydrophobic clusters as well as the coordination between these two interactions
Summary
Human immunodeficiency virus type 1 (HIV-1) protease is a symmetric homo-dimeric aspartyl protease, which cleaves the gag and pol viral polyproteins at its active site to process viral maturation [1]. To improve the efficacy of inhibitors, many efforts had been paid for studying the kinetic processes of association and dissociation of the interaction between inhibitors and the HIV-1 PR. Experimental results indicated that there are a wide range of association rate and dissociation rate constants in different inhibitors, e.g., kon&109,1010 M21s21 and koff &,100 s21 for cyclic urea inhibitors, while kon&105,106 M21s21 and koff &1023,1024 s21 for the approved inhibitors [3]. To understand these significant differences in the association rate and dissociation rate constants has been a primary impetus behind intensive studies
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