Back to Search Start Over

Investigation of Simultaneous and Sequential Cooperative Homotropic Inhibitor Binding to the Catalytic Chamber of SARS-CoV-2 RNA-dependent RNA Polymerase (RdRp).

Authors :
Metwally, Kamel
Abo-Dya, Nader E.
Hamdan, Ahmed M. E.
Alrashidi, Maram N.
Alturki, Mansour S.
Aly, Omar M.
Aljoundi, Aimen
Ibrahim, Mahmoud
Soliman, Mahmoud E. S.
Source :
Cell Biochemistry & Biophysics; Dec2023, Vol. 81 Issue 4, p697-706, 10p
Publication Year :
2023

Abstract

In our previous report, the unique architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which harbours two distinctive binding sites, was fully characterized at molecular level. The significant differences in the two binding sites BS1 and BS2 in terms of binding pockets motif, as well as the preferential affinities of eight anti-viral drugs to each of the two binding sites were described. Recent Cryogenic Electron Microscopy (Cryo-EM) studies on the RdRp revealed that two suramin molecules, a SARS-CoV-2 inhibitor, bind to RdRp in two different sites with distinctive interaction landscape. Here, we provide the first account of investigating the combined inhibitor binding to both binding sites, and whether the binding of two inhibitors molecules concurrently is "Cooperative binding" or not. It should be noted that the binding of inhibitors to different sites do not necessary constitute mutually independent events, therefore, we investigated two scenarios to better understand cooperativity: simultaneous binding and sequential binding. It has been demonstrated by binding free energy calculations (MM/PBSA) and piecewise linear potential (PLP) interaction energy analysis that the co-binding of two suramin molecules is not cooperative in nature; rather, when compared to individual binding, both molecules adversely affect one another's binding affinities. This observation appeared to be primarily due to RdRp's rigidity, which prevented both ligands from fitting comfortably within the catalytic chamber. Instead, the suramin molecules showed a tendency to change their orientation within the binding pockets in order to maintain their binding to the protein, but at the expense of the ligand internal energies. Although co-binding resulted in the loss of several important key interactions, a few interactions were conserved, and these appear to be crucial in preserving the binding of ligands in the active site. The structural and mechanistic details of this study will be useful for future research on creating and developing RdRp inhibitors against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
10859195
Volume :
81
Issue :
4
Database :
Complementary Index
Journal :
Cell Biochemistry & Biophysics
Publication Type :
Academic Journal
Accession number :
173274342
Full Text :
https://doi.org/10.1007/s12013-023-01163-y