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Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design.
Zanetti-Polzi, Laura; Smith, Micholas Dean; Chipot, Chris; Gumbart, James C; Lynch, Diane L; Pavlova, Anna; Smith, Jeremy C; Daidone, Isabella.
  • Zanetti-Polzi L; Center S3, CNR Institute of Nanoscience, Via Campi 213/A, I-41125 Modena, Italy.
  • Smith MD; Department of Biochemistry, Molecular and Cellular Biology, The University of Tennessee, Knoxville, 309 Ken and Blaire Mossman Bldg., 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United States.
  • Chipot C; UMR 7019, Université de Lorraine, Laboratoire International Associé CNRS, 54506 Vandœuvre-lès-Nancy, France.
  • Gumbart JC; University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, Illinois 61801, United States.
  • Lynch DL; School of Physics, Georgia Institute of Technology, Atlanta Georgia 30332, United States.
  • Pavlova A; School of Physics, Georgia Institute of Technology, Atlanta Georgia 30332, United States.
  • Smith JC; School of Physics, Georgia Institute of Technology, Atlanta Georgia 30332, United States.
  • Daidone I; Department of Biochemistry, Molecular and Cellular Biology, The University of Tennessee, Knoxville, 309 Ken and Blaire Mossman Bldg., 1311 Cumberland Avenue, Knoxville, Tennessee 37996, United States.
J Phys Chem Lett ; 12(17): 4195-4202, 2021 May 06.
Article in English | MEDLINE | ID: covidwho-1387119
Semantic information from SemMedBD (by NLM)
1. Protons COEXISTS_WITH Peptide Hydrolases
Subject
Protons
Predicate
COEXISTS_WITH
Object
Peptide Hydrolases
2. Protons STIMULATES Peptide Hydrolases
Subject
Protons
Predicate
STIMULATES
Object
Peptide Hydrolases
3. Protons COEXISTS_WITH Peptide Hydrolases
Subject
Protons
Predicate
COEXISTS_WITH
Object
Peptide Hydrolases
4. Protons STIMULATES Peptide Hydrolases
Subject
Protons
Predicate
STIMULATES
Object
Peptide Hydrolases
ABSTRACT
The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the α-ketoamide 13b. We show that with the inhibitors the free energy cost to reach the charge-separated state of the active-site dyad is lower, with N3 inducing the most significant reduction. We also show that a few key sites (including specific water molecules) significantly enhance or reduce the thermodynamic feasibility of the PT reaction, with selective desolvation of the active site playing a crucial role. The approach presented is a cost-effective procedure to identify the enzyme regions that control the activation of the catalytic reaction and is thus also useful to guide the design of inhibitors.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Main subject: Protease Inhibitors / Drug Design / Viral Matrix Proteins / SARS-CoV-2 Subject: Protease Inhibitors / Drug Design / Viral Matrix Proteins / SARS-CoV-2 Type of study: Prognostic study Language: English Journal: J Phys Chem Lett Year: 2021

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Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Main subject: Protease Inhibitors / Drug Design / Viral Matrix Proteins / SARS-CoV-2 Subject: Protease Inhibitors / Drug Design / Viral Matrix Proteins / SARS-CoV-2 Type of study: Prognostic study Language: English Journal: J Phys Chem Lett Year: 2021
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