Different Enzyme Conformations Induce Different Mechanistic Traits in HIV-1 Protease

João T.S. Coimbra; Rui P.P. Neves; Ana V. Cunha; Maria J. Ramos; Pedro A. Fernandes

doi:10.1002/chem.202201066

Different Enzyme Conformations Induce Different Mechanistic Traits in HIV-1 Protease

João T.S. Coimbra
, Rui P.P. Neves
, Ana V. Cunha
, Maria J. Ramos
, Pedro A. Fernandes

Advanced Computing for Chemistry and Mat

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English
Article number	e202201066
Journal	Chemistry - A European Journal
Volume	28
Issue number	42
DOIs	https://doi.org/10.1002/chem.202201066
State	Published - Jul 26 2022

Funding

This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through the project UIDB/50006/2020 | UIDP/50006/2020. J. T. S. C. thanks FCT for funding through the Individual Call to Scientific Employment Stimulus (CEECIND/01374/2018). R. P. P. N. acknowledges funding from projects PTDC/QUI‐QFI/28714/2017 and UIDB/50006/2020 by FCT/MCTES. We acknowledge the access to the Oak Ridge Leadership Computing Facility (OLCF) resources through the Directors’ Discretion program under project CHM151. This research used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE‐AC05‐00OR22725. We thank Dr. Ana Rita Calixto for providing us with the inputs of the starting configurations of the system and Óscar Passos for technical assistance.

Keywords

aspartic proteases
enzyme catalysis
mechanistic divergence
molecular dynamics
quantum mechanics/molecular mechanics

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10.1002/chem.202201066

Cite this

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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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AU - Ramos, Maria J.

AU - Fernandes, Pedro A.

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KW - mechanistic divergence

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Different Enzyme Conformations Induce Different Mechanistic Traits in HIV-1 Protease

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