Abstract
Herein, we investigate the structure and flexibility of the hydrated SARS-CoV-2 main protease by means of 2.0 μs molecular dynamics (MD) simulations in explicit solvent. After having performed electrostatic pKa calculations on several X-ray structures, we consider both the native (unbound) configuration of the enzyme and its noncovalent complex with a model peptide, Ace-Ala-Val-Leu-Gln∼Ser-Nme, which mimics the polyprotein sequence recognized at the active site. For each configuration, we also study their monomeric and homodimeric forms. The simulations of the unbound systems show that the relative orientation of domain III is not stable in the monomeric form and provide further details about interdomain motions, protomer-protomer interactions, inter-residue contacts, accessibility at the catalytic site, etc. In the presence of the peptide substrate, the monomeric protease exhibits a stable interdomain arrangement, but the relative orientation between the scissile peptide bond and the catalytic dyad is not favorable for catalysis. By means of comparative analysis, we further assess the catalytic impact of the enzyme dimerization, the actual flexibility of the active site region, and other structural effects induced by substrate...Continue Reading
References
Dec 1, 1983·Biopolymers·W Kabsch, C Sander
Aug 23, 2001·Proceedings of the National Academy of Sciences of the United States of America·N A BakerJ A McCammon
Oct 31, 2003·Proceedings of the National Academy of Sciences of the United States of America·Haitao YangZihe Rao
Mar 24, 2004·The Journal of Biological Chemistry·Jiahai ShiJianxing Song
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Oct 28, 2004·The Journal of Biological Chemistry·Shuai ChenXu Shen
Dec 22, 2004·Current Topics in Microbiology and Immunology·J Ziebuhr
Feb 8, 2005·Proteins·Dimas Suárez, Martin J Field
Apr 16, 2005·The Journal of Biological Chemistry·Wen-Chi HsuGu-Gang Chang
Feb 16, 2006·The FEBS Journal·Jiahai Shi, Jianxing Song
Nov 6, 2007·The Journal of Biological Chemistry·Shuai ChenXu Shen
Feb 16, 2008·Archives of Biochemistry and Biophysics·Pei-Ying LinGu-Gang Chang
Feb 29, 2008·Journal of Virology·Jiahai ShiJianxing Song
Dec 18, 2008·Proteins·Peng ZhouZhicai Shang
May 5, 2009·Virology·Tiancen HuXu Shen
Sep 18, 2009·The Journal of Physical Chemistry. B·In Suk Joung, Thomas E Cheatham
Apr 8, 2010·Biophysical Journal·Shu-Chun ChengChi-Yuan Chou
May 10, 2012·Nucleic Acids Research·Ramu AnandakrishnanAlexey V Onufriev
Sep 21, 2013·Journal of Computational Chemistry·Ernesto SuárezDimas Suárez
Jul 22, 2014·The FEBS Journal·Rolf Hilgenfeld
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Jul 9, 2013·Journal of Chemical Theory and Computation·Daniel R Roe, Thomas E Cheatham
Nov 21, 2015·Journal of Chemical Theory and Computation·Dimas Suárez, Natalia Díaz
Nov 6, 2018·Nucleic Acids Research·UNKNOWN UniProt Consortium
Jan 25, 2020·The New England Journal of Medicine·Na ZhuUNKNOWN China Novel Coronavirus Investigating and Research Team
Mar 4, 2020·Nature Microbiology·UNKNOWN Coronaviridae Study Group of the International Committee on Taxonomy of Viruses
Apr 10, 2020·Nature·Zhenming JinHaitao Yang
May 14, 2020·ACS Combinatorial Science·Bhupesh Goyal, Deepti Goyal
Citations
Feb 3, 2021·Journal of Biomolecular Structure & Dynamics·Mustafa Tekpinar, Ahmet Yildirim
Feb 11, 2021·Colloids and Surfaces. A, Physicochemical and Engineering Aspects·Kazushige Yokoyama, Akane Ichiki
Apr 3, 2021·Scientific Reports·Ying Li WengAravindhan Ganesan
Oct 19, 2020·European Journal of Pharmacology·Srichandan PadhiAntonio Evidente
Apr 13, 2021·Molecular Diversity·Shovonlal BhowmickMd Ataul Islam
Apr 27, 2021·The Journal of Physical Chemistry Letters·Laura Zanetti-PolziIsabella Daidone
May 1, 2021·Biomedicines·Bruno RizzutiAdrian Velazquez-Campoy
May 5, 2021·Chemical Communications : Chem Comm·Natalia Díaz, Dimas Suárez
May 11, 2021·Journal of Biomolecular Structure & Dynamics·Rafael E O RochaLeonardo H F de Lima
May 28, 2021·Frontiers in Molecular Biosciences·Shafi MahmudMd Abu Saleh
Jun 8, 2021·Journal of Chemical Information and Modeling·Daniel J EvansAlbert Y Lau
May 25, 2021·Journal of Traditional and Complementary Medicine·Ahmed A ZakiAhmed A Al-Karmalawy
Jun 15, 2021·Journal of Chemical Information and Modeling·Eunice ChoShozeb Haider
Jun 15, 2021·The Journal of Physical Chemistry. B·Shigenori TanakaYuji Mochizuki
Jun 26, 2021·Molecular Diversity·Henrique S FernandesNuno M F S A Cerqueira
Jul 9, 2021·BBA Advances·Shinji Iida, Yoshifumi Fukunishi
Jul 20, 2021·Journal of Chemical Information and Modeling·Jingyi YangWeiwei Xue
Jun 19, 2021·ChemMedChem·Ulises Martínez-OrtegaRodrigo Aguayo-Ortiz
Jul 31, 2021·Scientific Reports·Gabriel Jiménez-AvalosUNKNOWN COVID-19 Working Group in Perú
Jul 29, 2021·The Journal of Physical Chemistry. B·Aditya K PadhiTimir Tripathi
Aug 6, 2021·PLoS Computational Biology·Natália TeruelRafael J Najmanovich
Jan 1, 2021·Journal of Chemical Information and Modeling·Adrian J Mulholland, Rommie E Amaro
Aug 18, 2021·Structure·Serdar DurdagiHasan DeMirci
Dec 30, 2020·ACS Nano·Nikhil PathakJinn-Moon Yang
Aug 28, 2020·Journal of Chemical Information and Modeling·Olivier Sheik AmamuddyÖzlem Tastan Bishop
Aug 28, 2021·Antibiotics·Muhammad Fayyaz Ur RehmanMehwish Aslam
Oct 30, 2020·Journal of Proteome Research·Antonio Francés-MonerrisAntonio Monari
Sep 1, 2021·Current Opinion in Virology·Peter Eugene JonesJodi A Hadden-Perilla
Sep 14, 2021·Journal of Biomolecular Structure & Dynamics·Glaucio Monteiro FerreiraAntti Poso
Oct 28, 2021·Journal of Medicinal Chemistry·Daniel W KnellerAndrey Kovalevsky
Sep 28, 2021·Angewandte Chemie·François-Xavier CantrelleXavier Hanoulle