Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 28, Issue 42, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202201066
Keywords
aspartic proteases; enzyme catalysis; mechanistic divergence; molecular dynamics; quantum mechanics/molecular mechanics
Categories
Funding
- PT national funds (FCT/MCTES, FundacAo para a Ciencia e Tecnologia and Ministerio da Ciencia, Tecnologia e Ensino Superior) [UIDB/50006/2020 \ UIDP/50006/2020]
- FCT [CEECIND/01374/2018]
- FCT/MCTES [PTDC/QUI-QFI/28714/2017, UIDB/50006/2020]
- Oak Ridge Leadership Computing Facility (OLCF) [CHM151]
- Office of Science of the U.S. Department of Energy [DE-AC05-00OR22725]
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This study investigates the influence of enzyme's dynamical flexibility on reaction mechanisms, using the first step of HIV-1 protease catalyzed reaction as a case study. The results reveal a mechanistic divergence in the enzyme, with two different reaction pathways exhibiting equivalent barriers. An active-site water molecule is suggested to play a role in influencing the mechanistic pathway.
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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