Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

The main protease (M pro ) 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 M pro , a cysteine protease, have been determined, facilitating structure-based drug design. M pro 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, M pro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV M pro , 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 M pro 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 M pro 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 M pro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

Errataetall:

UpdateIn: Chem Sci. 2020 Nov 26;12(4):1513-1527. - PMID 35356437

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - year:2020

Enthalten in:

bioRxiv : the preprint server for biology - (2020) vom: 10. Sept.

Sprache:

Englisch

Beteiligte Personen:

Pavlova, Anna [VerfasserIn]
Lynch, Diane L [VerfasserIn]
Daidone, Isabella [VerfasserIn]
Zanetti-Polzi, Laura [VerfasserIn]
Smith, Micholas Dean [VerfasserIn]
Chipot, Chris [VerfasserIn]
Kneller, Daniel W [VerfasserIn]
Kovalevsky, Andrey [VerfasserIn]
Coates, Leighton [VerfasserIn]
Golosov, Andrei A [VerfasserIn]
Dickson, Callum J [VerfasserIn]
Velez-Vega, Camilo [VerfasserIn]
Duca, José S [VerfasserIn]
Vermaas, Josh V [VerfasserIn]
Pang, Yui Tik [VerfasserIn]
Acharya, Atanu [VerfasserIn]
Parks, Jerry M [VerfasserIn]
Smith, Jeremy C [VerfasserIn]
Gumbart, James C [VerfasserIn]

Links:

Volltext

Themen:

Preprint

Anmerkungen:

Date Revised 01.04.2022

published: Electronic

UpdateIn: Chem Sci. 2020 Nov 26;12(4):1513-1527. - PMID 35356437

Citation Status PubMed-not-MEDLINE

doi:

10.1101/2020.09.07.286344

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM315069880