Your browser doesn't support javascript.
Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease.
Pavlova, Anna; Lynch, Diane L; Daidone, Isabella; Zanetti-Polzi, Laura; Smith, Micholas Dean; Chipot, Chris; Kneller, Daniel W; Kovalevsky, Andrey; Coates, Leighton; Golosov, Andrei A; Dickson, Callum J; Velez-Vega, Camilo; Duca, José S; Vermaas, Josh V; Pang, Yui Tik; Acharya, Atanu; Parks, Jerry M; Smith, Jeremy C; Gumbart, James C.
  • Pavlova A; School of Physics, Georgia Institute of Technology Atlanta GA 30332 USA gumbart@physics.gatech.edu.
  • Lynch DL; School of Physics, Georgia Institute of Technology Atlanta GA 30332 USA gumbart@physics.gatech.edu.
  • Daidone I; Department of Physical and Chemical Sciences, University of L'Aquila I-67010 L'Aquila Italy.
  • Zanetti-Polzi L; CNR Institute of Nanoscience I-41125 Modena Italy.
  • Smith MD; Department of Biochemistry, Molecular and Cellular Biology, The University of Tennessee 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue Knoxville TN 37996 USA.
  • Chipot C; Université de Lorraine, UMR 7019, Laboratoire International Associé CNRS and University of Illinois at Urbana-Champaign Vandoeuvre-lès-Nancy F-54500 France.
  • Kneller DW; Department of Physics, University of Illinois at Urbana-Champaign 1110 West Green Street Urbana IL 61801 USA.
  • Kovalevsky A; Neutron Scattering Division, Oak Ridge National Laboratory 1 Bethel Valley Rd Oak Ridge TN 37831 USA.
  • Coates L; Neutron Scattering Division, Oak Ridge National Laboratory 1 Bethel Valley Rd Oak Ridge TN 37831 USA.
  • Golosov AA; Neutron Scattering Division, Oak Ridge National Laboratory 1 Bethel Valley Rd Oak Ridge TN 37831 USA.
  • Dickson CJ; Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research 181 Massachusetts Avenue Cambridge Massachusetts 02139 USA.
  • Velez-Vega C; Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research 181 Massachusetts Avenue Cambridge Massachusetts 02139 USA.
  • Duca JS; Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research 181 Massachusetts Avenue Cambridge Massachusetts 02139 USA.
  • Vermaas JV; Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research 181 Massachusetts Avenue Cambridge Massachusetts 02139 USA.
  • Pang YT; National Center for Computational Sciences, Oak Ridge National Laboratory Oak Ridge TN 37831 USA.
  • Acharya A; School of Physics, Georgia Institute of Technology Atlanta GA 30332 USA gumbart@physics.gatech.edu.
  • Parks JM; School of Physics, Georgia Institute of Technology Atlanta GA 30332 USA gumbart@physics.gatech.edu.
  • Smith JC; UT/ORNL Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory TN 37831 USA.
  • Gumbart JC; Department of Biochemistry, Molecular and Cellular Biology, The University of Tennessee 309 Ken and Blaire Mossman Bldg. 1311 Cumberland Avenue Knoxville TN 37996 USA.
Chem Sci ; 12(4): 1513-1527, 2021 Jan 28.
Article in English | MEDLINE | ID: covidwho-1083334
ABSTRACT
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nucleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N δ (HD) and N ϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

Full text: Available Collection: International databases Database: MEDLINE Language: English Journal: Chem Sci Year: 2021 Document Type: Article

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Language: English Journal: Chem Sci Year: 2021 Document Type: Article