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

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

doi:10.1002/chem.202201066

Title: Different Enzyme Conformations Induce Different Mechanistic Traits in HIV‐1 Protease

Journal Article · 26 June 2022 · Chemistry - A European Journal

DOI: https://doi.org/10.1002/chem.202201066 · OSTI ID:1873933

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LAQV/REQUIMTE Departamento de Química e Bioquímica Faculdade de Ciências Universidade do Porto Rua do Campo Alegre, s/n 4169-007 Porto Portugal
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

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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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1873933

Journal Information:: Chemistry - A European Journal, Journal Name: Chemistry - A European Journal Journal Issue: 42 Vol. 28; ISSN 0947-6539

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

References (40)

Towards the Accurate Thermodynamic Characterization of Enzyme Reaction Mechanisms Neves, Rui P. P.; Cunha, Ana V.; Fernandes, Pedro A. ChemPhysChem, Vol. 23, Issue 13 https://doi.org/10.1002/cphc.202200159	journal	May 2022
Multiscale modeling of enzymes: QM-cluster, QM/MM, and QM/MM/MD: A tutorial review Ahmadi, Shideh; Barrios Herrera, Lizandra; Chehelamirani, Morteza International Journal of Quantum Chemistry, Vol. 118, Issue 9 https://doi.org/10.1002/qua.25558	journal	January 2018
Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms: Application of QM/MM methods Sousa, Sérgio Filipe; Ribeiro, António J. M.; Neves, Rui P. P. Wiley Interdisciplinary Reviews: Computational Molecular Science, Vol. 7, Issue 2 https://doi.org/10.1002/wcms.1281	journal	September 2016
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Role of Conformational Fluctuations in the Enzymatic Reaction of HIV-1 Protease Piana, Stefano; Carloni, Paolo; Parrinello, Michele Journal of Molecular Biology, Vol. 319, Issue 2 https://doi.org/10.1016/S0022-2836(02)00301-7	journal	May 2002
Quickstep: Fast and accurate density functional calculations using a mixed Gaussian and plane waves approach VandeVondele, Joost; Krack, Matthias; Mohamed, Fawzi Computer Physics Communications, Vol. 167, Issue 2 https://doi.org/10.1016/j.cpc.2004.12.014	journal	April 2005
On the nature of the reaction intermediate in the HIV-1 protease: a quantum chemical study Carnevale, V.; Raugei, S.; Piana, S. Computer Physics Communications, Vol. 179, Issue 1-3 https://doi.org/10.1016/j.cpc.2008.01.032	journal	July 2008
Influence of Frozen Residues on the Exploration of the PES of Enzyme Reaction Mechanisms Calixto, Ana R.; Ramos, Maria J.; Fernandes, Pedro A. Journal of Chemical Theory and Computation, Vol. 13, Issue 11 https://doi.org/10.1021/acs.jctc.7b00768	journal	October 2017
How Many Conformations Need To Be Sampled To Obtain Converged QM/MM Energies? The Curse of Exponential Averaging Ryde, Ulf Journal of Chemical Theory and Computation, Vol. 13, Issue 11 https://doi.org/10.1021/acs.jctc.7b00826	journal	October 2017
Enzymatic Flexibility and Reaction Rate: A QM/MM Study of HIV-1 Protease Ribeiro, António J. M.; Santos-Martins, Diogo; Russo, Nino ACS Catalysis, Vol. 5, Issue 9 https://doi.org/10.1021/acscatal.5b00759	journal	August 2015
Mechanistic Studies of a Flavin Monooxygenase: Sulfur Oxidation of Dibenzothiophenes by DszC Barbosa, Ana C. C.; Neves, Rui P. P.; Sousa, Sérgio F. ACS Catalysis, Vol. 8, Issue 10 https://doi.org/10.1021/acscatal.8b01877	journal	September 2018
Inhibiting HTLV-1 Protease: A Viable Antiviral Target Lockbaum, Gordon J.; Henes, Mina; Talledge, Nathaniel ACS Chemical Biology, Vol. 16, Issue 3 https://doi.org/10.1021/acschembio.0c00975	journal	February 2021
Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance Henes, Mina; Lockbaum, Gordon J.; Kosovrasti, Klajdi ACS Chemical Biology, Vol. 14, Issue 11 https://doi.org/10.1021/acschembio.9b00370	journal	July 2019
Visualizing Tetrahedral Oxyanion Bound in HIV-1 Protease Using Neutrons: Implications for the Catalytic Mechanism and Drug Design Kumar, Mukesh; Mandal, Kalyaneswar; Blakeley, Matthew P. ACS Omega, Vol. 5, Issue 20 https://doi.org/10.1021/acsomega.0c00835	journal	May 2020
Follow the Protons: A Low-Barrier Hydrogen Bond Unifies the Mechanisms of the Aspartic Proteases Northrop, Dexter B. Accounts of Chemical Research, Vol. 34, Issue 10 https://doi.org/10.1021/ar000184m	journal	October 2001
Use of nitrogen-15 kinetic isotope effects to elucidate details of the chemical mechanism of human immunodeficiency virus 1 protease Rodriguez, Evelyn J.; Angeles, Thelma S.; Meek, Thomas D. Biochemistry, Vol. 32, Issue 46 https://doi.org/10.1021/bi00097a015	journal	November 1993
Human immunodeficiency virus-1 protease. 1. Initial velocity studies and kinetic characterization of reaction intermediates by oxygen-18 isotope exchange Hyland, Lawrence J.; Tomaszek, Thaddeus A.; Roberts, Gerald D. Biochemistry, Vol. 30, Issue 34 https://doi.org/10.1021/bi00098a023	journal	August 1991
Human immunodeficiency virus-1 protease. 2. Use of pH rate studies and solvent kinetic isotope effects to elucidate details of chemical mechanism Hyland, Lawrence J.; Tomaszek, Thaddeus A.; Meek, Thomas D. Biochemistry, Vol. 30, Issue 34 https://doi.org/10.1021/bi00098a024	journal	August 1991
Single Molecule Studies of Enzyme Mechanisms Smiley, R. Derike; Hammes, Gordon G. Chemical Reviews, Vol. 106, Issue 8 https://doi.org/10.1021/cr0502955	journal	August 2006
The ONIOM Method and Its Applications Chung, Lung Wa; Sameera, W. M. C.; Ramozzi, Romain Chemical Reviews, Vol. 115, Issue 12 https://doi.org/10.1021/cr5004419	journal	April 2015
Convergent Dynamics in the Protease Enzymatic Superfamily Carnevale, Vincenzo; Raugei, Simone; Micheletti, Cristian Journal of the American Chemical Society, Vol. 128, Issue 30 https://doi.org/10.1021/ja060896t	journal	August 2006
Unraveling the Enigmatic Mechanism of l -Asparaginase II with QM/QM Calculations Gesto, Diana S.; Cerqueira, Nuno M. F. S. A.; Fernandes, Pedro A. Journal of the American Chemical Society, Vol. 135, Issue 19 https://doi.org/10.1021/ja310165u	journal	May 2013
Hydrolysis Mechanism of the Phenylalanine−Proline Peptide Bond Specific to HIV-1 Protease: Investigation by the ab Initio Molecular Orbital Method Okimoto, Noriaki; Tsukui, Toshiyuki; Hata, Masayuki Journal of the American Chemical Society, Vol. 121, Issue 32 https://doi.org/10.1021/ja9841106	journal	July 1999
Dynamic and Electrostatic Effects on the Reaction Catalyzed by HIV-1 Protease Krzemińska, Agnieszka; Moliner, Vicent; Świderek, Katarzyna Journal of the American Chemical Society, Vol. 138, Issue 50 https://doi.org/10.1021/jacs.6b06856	journal	December 2016
Reaction Mechanism of HIV-1 Protease by Hybrid Car-Parrinello/Classical MD Simulations Piana, Stefano; Bucher, Denis; Carloni, Paolo The Journal of Physical Chemistry B, Vol. 108, Issue 30 https://doi.org/10.1021/jp037651c	journal	July 2004
Understanding the HIV-1 Protease Reactivity with DFT: What Do We Gain from Recent Functionals? Garrec, J.; Sautet, P.; Fleurat-Lessard, P. The Journal of Physical Chemistry B, Vol. 115, Issue 26 https://doi.org/10.1021/jp200565w	journal	June 2011
Differences in the chemical reactivity of individual molecules of an enzyme Xue, Qifeng; Yeung, Edward S. Nature, Vol. 373, Issue 6516 https://doi.org/10.1038/373681a0	journal	February 1995
QM/MM simulations as an assay for carbapenemase activity in class A β-lactamases Chudyk, Ewa I.; Limb, Michael A. L.; Jones, Charlotte Chem. Commun., Vol. 50, Issue 94 https://doi.org/10.1039/C4CC06495J	journal	January 2014
Conformational diversity induces nanosecond-timescale chemical disorder in the HIV-1 protease reaction pathway Calixto, Ana Rita; Ramos, Maria João; Fernandes, Pedro Alexandrino Chemical Science, Vol. 10, Issue 30 https://doi.org/10.1039/C9SC01464K	journal	January 2019
A practical guide to modelling enzyme-catalysed reactions Lonsdale, Richard; Harvey, Jeremy N.; Mulholland, Adrian J. Chemical Society Reviews, Vol. 41, Issue 8 https://doi.org/10.1039/c2cs15297e	journal	January 2012
Ionization state of the catalytic dyad Asp25/25′ in the HIV-1 protease: NMR studies of site-specifically 13C labelled HIV-1 protease prepared by total chemical synthesis Torbeev, Vladimir Yu.; Kent, Stephen B. H. Organic & Biomolecular Chemistry, Vol. 10, Issue 30 https://doi.org/10.1039/c2ob25569c	journal	January 2012
Canonical sampling through velocity rescaling Bussi, Giovanni; Donadio, Davide; Parrinello, Michele The Journal of Chemical Physics, Vol. 126, Issue 1 https://doi.org/10.1063/1.2408420	journal	January 2007
CP2K: An electronic structure and molecular dynamics software package - Quickstep: Efficient and accurate electronic structure calculations Kühne, Thomas D.; Iannuzzi, Marcella; Del Ben, Mauro The Journal of Chemical Physics, Vol. 152, Issue 19 https://doi.org/10.1063/5.0007045	journal	May 2020
Transition states of native and drug-resistant HIV-1 protease are the same Kipp, D. R.; Hirschi, J. S.; Wakata, A. Proceedings of the National Academy of Sciences, Vol. 109, Issue 17 https://doi.org/10.1073/pnas.1202808109	journal	April 2012
Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase Neves, Rui P. P.; Fernandes, Pedro Alexandrino; Ramos, Maria João Proceedings of the National Academy of Sciences, Vol. 114, Issue 24 https://doi.org/10.1073/pnas.1618985114	journal	May 2017
Exploration of the effects of sequence variations between HIV-1 and HIV-2 proteases on their three-dimensional structures Triki, Dhoha; Kermarrec, Maxime; Visseaux, Benoît Journal of Biomolecular Structure and Dynamics, Vol. 38, Issue 17 https://doi.org/10.1080/07391102.2019.1704877	journal	December 2019
Exploring the concerted mechanistic pathway for HIV-1 PR—substrate revealed by umbrella sampling simulation Sanusi, Zainab K.; Lawal, Monsurat M.; Gupta, Pancham Lal. Journal of Biomolecular Structure and Dynamics, Vol. 40, Issue 4 https://doi.org/10.1080/07391102.2020.1832578	journal	October 2020
Separable dual-space Gaussian pseudopotentials Goedecker, S.; Teter, M.; Hutter, J. Physical Review B, Vol. 54, Issue 3 https://doi.org/10.1103/PhysRevB.54.1703	journal	July 1996
Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution Miller, M.; Schneider, J.; Sathyanarayana, B. Science, Vol. 246, Issue 4934 https://doi.org/10.1126/science.2686029	journal	December 1989
QM Cluster or QM/MM in Computational Enzymology: The Test Case of LigW-Decarboxylase Prejanò, Mario; Marino, Tiziana; Russo, Nino Frontiers in Chemistry, Vol. 6 https://doi.org/10.3389/fchem.2018.00249	journal	June 2018

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