Different Enzyme Conformations Induce Different Mechanistic Traits in HIV-1 Protease |
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| Authors: | Dr João T S Coimbra Dr Rui P P Neves Prof Dr Ana V Cunha Prof Dr Maria J Ramos Prof Dr Pedro A Fernandes |
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| Institution: | 1. LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências Universidade do Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal;2. Scientific Computing Group, Oak Ridge National Laboratory, 1 Bethel Valley Rd, 37831-6373 Oak Ridge, TN, USA
Presnt address: Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium |
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| Abstract: | The influence of the dynamical flexibility of enzymes on reaction mechanisms is a cornerstone in biological sciences. In this study, we aim to 1) study the convergence of the activation free energy by using the first step of the reaction catalysed by HIV-1 protease as a case study, and 2) provide further evidence for a mechanistic divergence in this enzyme, as two different reaction pathways were seen to contribute to this step. We used quantum mechanics/molecular mechanics molecular dynamics simulations, on four different initial conformations that led to different barriers in a previous study. Despite the sampling, the four activation free energies still spanned a range of 5.0 kcal ⋅ mol−1. Furthermore, the new simulations did confirm the occurrence of an unusual mechanistic divergence, with two different mechanistic pathways displaying equivalent barriers. An active-site water molecule is proposed to influence the mechanistic pathway. |
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| Keywords: | aspartic proteases enzyme catalysis mechanistic divergence molecular dynamics quantum mechanics/molecular mechanics |
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