Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Naseem-Khan, Sehr; Berger, Madison B.; Leddin, Emmett M.; Maghsoud, Yazdan; Cisneros, G. Andrés

doi:10.1021/acs.jcim.2c00201

Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Journal Article · Mon Apr 18 00:00:00 EDT 2022 · Journal of Chemical Information and Modeling

DOI:https://doi.org/10.1021/acs.jcim.2c00201· OSTI ID:1981871

^[1]; ^[2]; ^[1]; Maghsoud, Yazdan ^[2]; ^[2]

University of North Texas, Denton, TX (United States)
University of North Texas, Denton, TX (United States); University of Texas at Dallas, Richardson, TX (United States)

Remdesivir was the first antiviral drug that received emergency use authorization from the United States Food and Drug Administration and is now formally approved to treat COVID-19. Remdesivir is a nucleotide analogue that targets the RNA-dependent RNA polymerase (RdRp) of coronaviruses, including SARS-CoV-2. The solution of multiple RdRp structures has been one of the main axes of research in the race against the SARS-CoV-2 virus. Several hypotheses of the mechanism of inhibition of RdRp by remdesivir have been proposed, although open questions remain. This work uses molecular dynamics simulations to explore the impact of remdesivir and two analogues as incoming nucleotides and of up to four incorporations of remdesivir along the primer strand on RdRp. The simulation results suggest that the overall structure and the dynamical behavior of RdRp are destabilized by remdesivir and the two analogues in the incoming position. The incorporation of remdesivir along the primer strand impacts specific non-bonded interactions between the nascent RNA and the polymerase subunit, as well as the overall dynamical networks on RdRp. The strongest impact on the structure and dynamics are observed after three incorporations, when remdesivir is located at position -A3, in agreement with previously reported experimental and computational results. Our results provide atomic-level details of the role played by remdesivir on the disruption of RNA synthesis by RdRp and the main drivers of these disruptions.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); University of North Texas, Denton, TX (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1981871

Journal Information:: Journal of Chemical Information and Modeling, Journal Name: Journal of Chemical Information and Modeling Journal Issue: 10 Vol. 62; ISSN 1549-9596

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

References (69)

Development of polyphosphate parameters for use with the AMBER force field Meagher, Kristin L.; Redman, Luke T.; Carlson, Heather A. Journal of Computational Chemistry, Vol. 24, Issue 9 https://doi.org/10.1002/jcc.10262	journal	July 2003
UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Free Energy Calculations by the Molecular Mechanics Poisson−Boltzmann Surface Area Method Homeyer, Nadine; Gohlke, Holger Molecular Informatics, Vol. 31, Issue 2 https://doi.org/10.1002/minf.201100135	journal	January 2012
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
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein Walls, Alexandra C.; Park, Young-Jun; Tortorici, M. Alejandra Cell, Vol. 181, Issue 2 https://doi.org/10.1016/j.cell.2020.02.058	journal	April 2020
Binding of 2′-Amino-2′-Deoxycytidine-5′-Triphosphate to Norovirus Polymerase Induces Rearrangement of the Active Site Zamyatkin, Dmitry F.; Parra, Francisco; Machín, Ángeles Journal of Molecular Biology, Vol. 390, Issue 1 https://doi.org/10.1016/j.jmb.2009.04.069	journal	July 2009
Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial Ella, Raches; Reddy, Siddarth; Blackwelder, William The Lancet, Vol. 398, Issue 10317 https://doi.org/10.1016/s0140-6736(21)02000-6	journal	December 2021
Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial Xia, Shengli; Zhang, Yuntao; Wang, Yanxia The Lancet Infectious Diseases, Vol. 21, Issue 1 https://doi.org/10.1016/s1473-3099(20)30831-8	journal	January 2021
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial Zhang, Yanjun; Zeng, Gang; Pan, Hongxing The Lancet Infectious Diseases, Vol. 21, Issue 2 https://doi.org/10.1016/s1473-3099(20)30843-4	journal	February 2021
NCIPLOT4: Fast, Robust, and Quantitative Analysis of Noncovalent Interactions Boto, Roberto A.; Peccati, Francesca; Laplaza, Rubén Journal of Chemical Theory and Computation, Vol. 16, Issue 7 https://doi.org/10.1021/acs.jctc.0c00063	journal	May 2020
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik Journal of Chemical Theory and Computation, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jctc.5b00255	journal	July 2015
Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1- f ][triazin-4-amino] Adenine C -Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses Siegel, Dustin; Hui, Hon C.; Doerffler, Edward Journal of Medicinal Chemistry, Vol. 60, Issue 5 https://doi.org/10.1021/acs.jmedchem.6b01594	journal	January 2017
Structural Basis of the Potential Binding Mechanism of Remdesivir to SARS-CoV-2 RNA-Dependent RNA Polymerase Zhang, Leili; Zhou, Ruhong The Journal of Physical Chemistry B, Vol. 124, Issue 32 https://doi.org/10.1021/acs.jpcb.0c04198	journal	June 2020
Insights into the Inhibitory Mechanism of D13-9001 to the Multidrug Transporter AcrB through Molecular Dynamics Simulations Zuo, Zhicheng; Weng, Jingwei; Wang, Wenning The Journal of Physical Chemistry B, Vol. 120, Issue 9 https://doi.org/10.1021/acs.jpcb.5b11942	journal	March 2016
Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19 Eastman, Richard T.; Roth, Jacob S.; Brimacombe, Kyle R. ACS Central Science, Vol. 6, Issue 5 https://doi.org/10.1021/acscentsci.0c00489	journal	May 2020
Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase Byléhn, Fabian; Menéndez, Cintia A.; Perez-Lemus, Gustavo R. ACS Central Science, Vol. 7, Issue 1 https://doi.org/10.1021/acscentsci.0c01242	journal	January 2021
Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models Kollman, Peter A.; Massova, Irina; Reyes, Carolina Accounts of Chemical Research, Vol. 33, Issue 12 https://doi.org/10.1021/ar000033j	journal	December 2000
Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations Hou, Tingjun; Wang, Junmei; Li, Youyong Journal of Chemical Information and Modeling, Vol. 51, Issue 1 https://doi.org/10.1021/ci100275a	journal	November 2010
Structural Survey of Zinc-Containing Proteins and Development of the Zinc AMBER Force Field (ZAFF) Peters, Martin B.; Yang, Yue; Wang, Bing Journal of Chemical Theory and Computation, Vol. 6, Issue 9 https://doi.org/10.1021/ct1002626	journal	August 2010
Performance of Molecular Mechanics Force Fields for RNA Simulations: Stability of UUCG and GNRA Hairpins Banáš, Pavel; Hollas, Daniel; Zgarbová, Marie Journal of Chemical Theory and Computation, Vol. 6, Issue 12 https://doi.org/10.1021/ct100481h	journal	November 2010
NCIPLOT: A Program for Plotting Noncovalent Interaction Regions Contreras-García, Julia; Johnson, Erin R.; Keinan, Shahar Journal of Chemical Theory and Computation, Vol. 7, Issue 3 https://doi.org/10.1021/ct100641a	journal	January 2011
Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles Zgarbová, Marie; Otyepka, Michal; Šponer, Jiří Journal of Chemical Theory and Computation, Vol. 7, Issue 9 https://doi.org/10.1021/ct200162x	journal	August 2011
MMPBSA.py : An Efficient Program for End-State Free Energy Calculations Miller, Bill R.; McGee, T. Dwight; Swails, Jason M. Journal of Chemical Theory and Computation, Vol. 8, Issue 9 https://doi.org/10.1021/ct300418h	journal	August 2012
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data Roe, Daniel R.; Cheatham, Thomas E. Journal of Chemical Theory and Computation, Vol. 9, Issue 7 https://doi.org/10.1021/ct400341p	journal	June 2013
A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model Bayly, Christopher I.; Cieplak, Piotr; Cornell, Wendy The Journal of Physical Chemistry, Vol. 97, Issue 40 https://doi.org/10.1021/j100142a004	journal	October 1993
Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys Warren, Travis K.; Jordan, Robert; Lo, Michael K. Nature, Vol. 531, Issue 7594 https://doi.org/10.1038/nature17180	journal	March 2016
Identification of a unique Ca2+-binding site in rat acid-sensing ion channel 3 Zuo, Zhicheng; Smith, Rachel N.; Chen, Zhenglan Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-04424-0	journal	May 2018
Mechanism of SARS-CoV-2 polymerase stalling by remdesivir Kokic, Goran; Hillen, Hauke S.; Tegunov, Dimitry Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-020-20542-0	journal	January 2021
A glycan gate controls opening of the SARS-CoV-2 spike protein Sztain, Terra; Ahn, Surl-Hee; Bogetti, Anthony T. Nature Chemistry, Vol. 13, Issue 10 https://doi.org/10.1038/s41557-021-00758-3	journal	August 2021
Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors Jin, Zhenming; Du, Xiaoyu; Xu, Yechun Nature, Vol. 582, Issue 7811 https://doi.org/10.1038/s41586-020-2223-y	journal	April 2020
Structure of replicating SARS-CoV-2 polymerase Hillen, Hauke S.; Kokic, Goran; Farnung, Lucas Nature, Vol. 584, Issue 7819 https://doi.org/10.1038/s41586-020-2368-8	journal	May 2020
Structure and Dynamics of Cas9 HNH Domain Catalytic State Zuo, Zhicheng; Liu, Jin Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-17578-6	journal	December 2017
The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building Dupradeau, François-Yves; Pigache, Adrien; Zaffran, Thomas Physical Chemistry Chemical Physics, Vol. 12, Issue 28 https://doi.org/10.1039/c0cp00111b	journal	January 2010
1′-Ribose cyano substitution allows Remdesivir to effectively inhibit nucleotide addition and proofreading during SARS-CoV-2 viral RNA replication Zhang, Lu; Zhang, Dong; Wang, Xiaowei Physical Chemistry Chemical Physics, Vol. 23, Issue 10 https://doi.org/10.1039/d0cp05948j	journal	January 2021
Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 M ^pro by QM/MM computational methods Świderek, Katarzyna; Moliner, Vicent Chemical Science, Vol. 11, Issue 39 https://doi.org/10.1039/d0sc02823a	journal	January 2020
Compassionate Use of Remdesivir for Patients with Severe Covid-19 Grein, Jonathan; Ohmagari, Norio; Shin, Daniel New England Journal of Medicine, Vol. 382, Issue 24 https://doi.org/10.1056/nejmoa2007016	journal	June 2020
Remdesivir for the Treatment of Covid-19 — Final Report Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E. New England Journal of Medicine, Vol. 383, Issue 19 https://doi.org/10.1056/nejmoa2007764	journal	November 2020
Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results Pan, Hongchao; Peto, Richard; Karim, Quarraisha Abdool New England Journal of Medicine, Vol. 384, Issue 6, p. 497-511 https://doi.org/10.1056/nejmoa2023184	journal	February 2021
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Polack, Fernando P.; Thomas, Stephen J.; Kitchin, Nicholas New England Journal of Medicine, Vol. 383, Issue 27 https://doi.org/10.1056/nejmoa2034577	journal	December 2020
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Baden, Lindsey R.; El Sahly, Hana M.; Essink, Brandon New England Journal of Medicine, Vol. 384, Issue 5 https://doi.org/10.1056/nejmoa2035389	journal	February 2021
Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19 Sadoff, Jerald; Gray, Glenda; Vandebosch, An New England Journal of Medicine, Vol. 384, Issue 23 https://doi.org/10.1056/nejmoa2101544	journal	June 2021
Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine Falsey, Ann R.; Sobieszczyk, Magdalena E.; Hirsch, Ian New England Journal of Medicine, Vol. 385, Issue 25 https://doi.org/10.1056/nejmoa2105290	journal	December 2021
Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico Dunkle, Lisa M.; Kotloff, Karen L.; Gay, Cynthia L. New England Journal of Medicine, Vol. 386, Issue 6 https://doi.org/10.1056/nejmoa2116185	journal	February 2022
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
Molecular dynamics with coupling to an external bath Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F. The Journal of Chemical Physics, Vol. 81, Issue 8 https://doi.org/10.1063/1.448118	journal	October 1984
A smooth particle mesh Ewald method Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L. The Journal of Chemical Physics, Vol. 103, Issue 19 https://doi.org/10.1063/1.470117	journal	November 1995
Generalized correlation-based dynamical network analysis: a new high-performance approach for identifying allosteric communications in molecular dynamics trajectories Melo, Marcelo C. R.; Bernardi, Rafael C.; de la Fuente-Nunez, Cesar The Journal of Chemical Physics, Vol. 153, Issue 13 https://doi.org/10.1063/5.0018980	journal	October 2020
Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency Gordon, Calvin J.; Tchesnokov, Egor P.; Woolner, Emma Journal of Biological Chemistry, Vol. 295, Issue 20 https://doi.org/10.1074/jbc.ra120.013679	journal	May 2020
The interactions and recognition of cyclic peptide mimetics of Tat with HIV-1 TAR RNA: a molecular dynamics simulation study Li, Chun Hua; Zuo, Zhi Cheng; Su, Ji Guo Journal of Biomolecular Structure and Dynamics, Vol. 31, Issue 3 https://doi.org/10.1080/07391102.2012.698248	journal	March 2013
ProDy: Protein Dynamics Inferred from Theory and Experiments Bakan, A.; Meireles, L. M.; Bahar, I. Bioinformatics, Vol. 27, Issue 11, p. 1575-1577 https://doi.org/10.1093/bioinformatics/btr168	journal	April 2011
R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragments Vanquelef, Enguerran; Simon, Sabrina; Marquant, Gaelle Nucleic Acids Research, Vol. 39, Issue suppl_2 https://doi.org/10.1093/nar/gkr288	journal	May 2011
Nucleotide Prodrug GS-5734 Is a Broad-Spectrum Filovirus Inhibitor That Provides Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) in Infected Non-human Primates Warren, Travis; Jordan, Robert; Lo, Michale Open Forum Infectious Diseases, Vol. 2, Issue suppl_1 https://doi.org/10.1093/ofid/ofv130.02	journal	December 2015
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S. Science, Vol. 367, Issue 6483 https://doi.org/10.1126/science.abb2507	journal	February 2020
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors Zhang, Linlin; Lin, Daizong; Sun, Xinyuanyuan Science https://doi.org/10.1126/science.abb3405	journal	March 2020
Structure of the RNA-dependent RNA polymerase from COVID-19 virus Gao, Yan; Yan, Liming; Huang, Yucen Science, Vol. 368, Issue 6492 https://doi.org/10.1126/science.abb7498	journal	April 2020
Site-specific glycan analysis of the SARS-CoV-2 spike Watanabe, Yasunori; Allen, Joel D.; Wrapp, Daniel Science, Vol. 369, Issue 6501 https://doi.org/10.1126/science.abb9983	journal	May 2020
Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir Yin, Wanchao; Mao, Chunyou; Luan, Xiaodong Science, Vol. 368, Issue 6498 https://doi.org/10.1126/science.abc1560	journal	May 2020
Biomolecular Simulations: Recent Developments in Force Fields, Simulations of Enzyme Catalysis, Protein-Ligand, Protein-Protein, and Protein-Nucleic Acid Noncovalent Interactions Wang, Wei; Donini, Oreola; Reyes, Carolina M. Annual Review of Biophysics and Biomolecular Structure, Vol. 30, Issue 1 https://doi.org/10.1146/annurev.biophys.30.1.211	journal	June 2001
Gephi: An Open Source Software for Exploring and Manipulating Networks Bastian, Mathieu; Heymann, Sebastien; Jacomy, Mathieu Proceedings of the International AAAI Conference on Web and Social Media, Vol. 3, Issue 1 https://doi.org/10.1609/icwsm.v3i1.13937	journal	March 2009
Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models Wang, Junmei; Hou, Tingjun; Xu, Xiaojie Current Computer Aided-Drug Design, Vol. 2, Issue 3 https://doi.org/10.2174/157340906778226454	journal	September 2006
Norovirus polymerase+primer/template+CTP complex at 6 mM MnCl2 Zamyatkin, D. F.; Parra, F.; Machin, A. Worldwide Protein Data Bank https://doi.org/10.2210/pdb3h5y/pdb	text	January 2009
Structure of replicating SARS-CoV-2 polymerase Hillen, H. S.; Kokic, G.; Farnung, L. Worldwide Protein Data Bank https://doi.org/10.2210/pdb6yyt/pdb	text	January 2020
SARS-CoV-2 RNA-dependent RNA polymerase in complex with cofactors in reduced condition Gao, Y.; Yan, L.; Huang, Y. Worldwide Protein Data Bank https://doi.org/10.2210/pdb7btf/pdb	text	January 2020
Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease Mengist, Hylemariam Mihiretie; Dilnessa, Tebelay; Jin, Tengchuan Frontiers in Chemistry, Vol. 9 https://doi.org/10.3389/fchem.2021.622898	journal	March 2021
SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development Wang, Mei-Yue; Zhao, Rong; Gao, Li-Juan Frontiers in Cellular and Infection Microbiology, Vol. 10 https://doi.org/10.3389/fcimb.2020.587269	journal	November 2020
Directly Acting Antivirals for COVID-19: Where Do We Stand? Teoh, Siew L.; Lim, Yi H.; Lai, Nai M. Frontiers in Microbiology, Vol. 11 https://doi.org/10.3389/fmicb.2020.01857	journal	August 2020
Molecular Dynamics Simulations Reveal the Interaction Fingerprint of Remdesivir Triphosphate Pivotal in Allosteric Regulation of SARS-CoV-2 RdRp Srivastava, Mitul; Mittal, Lovika; Kumari, Anita Frontiers in Molecular Biosciences, Vol. 8 https://doi.org/10.3389/fmolb.2021.639614	journal	August 2021
SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors Citarella, Andrea; Scala, Angela; Piperno, Anna Biomolecules, Vol. 11, Issue 4 https://doi.org/10.3390/biom11040607	journal	April 2021
The interactions and recognition of cyclic peptide mimetics of Tat with HIV-1 TAR RNA: a molecular dynamics simulation study Li, Chun Hua; Zuo, Zhi Cheng; Su, Ji Guo Figshare https://doi.org/10.6084/m9.figshare.c.1888172	collection	January 2015

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