Unraveling HIV protease flaps dynamics by Constant pH Molecular Dynamics simulations.
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.
Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; Diretoria de Metrologia Aplicada às Ciências da Vida (DIMAV), Instituto Nacional de Metrologia Qualidade e Tecnologia (INMETRO), Xerém, Brazil. Electronic address: rosemberg@biof.ufrj.br.
Rosemberg O
RO
Soares
Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
Pedro H M
PHM
Torres
Diretoria de Metrologia Aplicada às Ciências da Vida (DIMAV), Instituto Nacional de Metrologia Qualidade e Tecnologia (INMETRO), Xerém, Brazil.
Manuela L
ML
da Silva
Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; Diretoria de Metrologia Aplicada às Ciências da Vida (DIMAV), Instituto Nacional de Metrologia Qualidade e Tecnologia (INMETRO), Xerém, Brazil.
Pedro G
PG
Pascutti
D001224:Aspartic Acid / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D006678:HIV / Q000737:chemistry*; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
D017320:HIV Protease Inhibitors; D001224:Aspartic Acid; D016333:HIV Protease
Constant pH Molecular Dynamics; Flaps; HIV protease; Protein conformation; pH