Unraveling HIV protease flaps dynamics by Constant pH Molecular Dynamics simulations

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• 作者：Rosemberg O. Soares^a ; ^b ; ^{rosemberg@biof.ufrj.br" class="auth_mail" title="E-mail the corresponding author} ; Pedro H.M. Torres^a ; Manuela L. da Silva^b ; Pedro G. Pascutti^a ; ^b
• 关键词：HIV-PR ; HIV protease ; MD ; standard molecular dynamics ; CpHMD ; Constant pH Molecular Dynamics ; PDB ; the Protein Data Bank ; GB ; Generalized Born method ; p1p6 ; p1p6 ; substrate ; NFV ; nelfinavir ; EM ; energy minimization ; PCA ; principal component analysis ; PC ; principal components ; EPR ; electron paramagnetic resonance ; DEER ; double electron-electron resonance ; LBHB ; low barrier hydrogen bonds
• 刊名：Journal of Structural Biology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：195
• 期：2
• 页码：216-226
• 全文大小：2145 K

文摘

The active site of HIV protease (HIV-PR) is covered by two flaps. These flaps are known to be essential for the catalytic activity of the HIV-PR, but their exact conformations at the different stages of the enzymatic pathway remain subject to debate. Understanding the correct functional dynamics of the flaps might aid the development of new HIV-PR inhibitors. It is known that, the HIV-PR catalytic efficiency is pH-dependent, likely due to the influence of processes such as charge transfer and protonation/deprotonation of ionizable residues. Several Molecular Dynamics (MD) simulations have reported information about the HIV-PR flaps. However, in MD simulations the protonation of a residue is fixed and thus it is not possible to study the correlation between conformation and protonation state. To address this shortcoming, this work attempts to capture, through Constant pH Molecular Dynamics (CpHMD), the conformations of the apo, substrate-bound and inhibitor-bound HIV-PR, which differ drastically in their flap arrangements. The results show that the HIV-PR flaps conformations are defined by the protonation of the catalytic residues Asp25/Asp25′ and that these residues are sensitive to pH changes. This study suggests that the catalytic aspartates can modulate the opening of the active site and substrate binding.