Characterization of the Conformational Hotspots of the RNA-Dependent RNA Polymerase Complex Identifies a Unique Structural Malleability of nsp8 DOI

Sowmomita Gharui,

Durba Sengupta, Atanu Das

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 2, 2024

Several antiviral therapeutic approaches have been targeted toward the RNA-dependent RNA polymerase (RdRp) complex that is involved in viral genome replication. In SARS-CoV-2, although RdRp a multiprotein complex, focus has on ligand binding catalytic core (nonstructural protein nsp12), and not functional dynamics. this study, we conformational ensembles of their modulation by presence RNA, performing comprehensive microsecond-scale atomistic simulations apo- RNA-bound complex. We delineate differential impact constituent proteins, such as polymorphisms, dominant segment-specific fluctuations, switch dynamical crosstalk within distinguish signatures nsp7, nsp8, nsp12 apo-state are reduced appear to "prime" for activity. Importantly, identify unique structural malleability nsp8 with high heterogeneity apo state, especially at three sites (Y71 nsp8A, D52 A66 nsp8B). Our work highlights implications polymorphism structures reveals possibilities development allosteric inhibitors.

Language: Английский

Eliminating Imaginary Vibrational Frequencies in Quantum-Chemical Cluster Models of Enzymatic Active Sites DOI
Paige E. Bowling, Saswata Dasgupta, John M. Herbert

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(9), P. 3912 - 3922

Published: April 22, 2024

In constructing finite models of enzyme active sites for quantum-chemical calculations, atoms at the periphery model must be constrained to prevent unphysical rearrangements during geometry relaxation. A simple fixed-atom or "coordinate-lock" approach is commonly employed but leads undesirable artifacts in form small imaginary frequencies. These preclude evaluation finite-temperature free-energy corrections, limiting thermochemical calculations enthalpies only. Full-dimensional vibrational frequency are possible by replacing constraints with harmonic confining potentials. Here, we compare that an alternative strategy which contributions Hessian simply omitted. While latter does eliminate frequencies, it tends underestimate both zero-point energy and entropy while introducing artificial rigidity. Harmonic potentials frequencies provide a flexible means construct active-site can used unconstrained relaxations, affording better convergence reaction energies barrier heights respect size, as compared constraints.

Language: Английский

Citations

9
Molecular dynamics simulations for the structure-based drug design: targeting small-GTPases proteins DOI
Angela Parise,

Sofia Cresca,

Alessandra Magistrato

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(10), P. 1259 - 1279

Published: Aug. 6, 2024

Molecular Dynamics (MD) simulations can support mechanism-based drug design. Indeed, MD by capturing biomolecule motions at finite temperatures reveal hidden binding sites, accurately predict drug-binding poses, and estimate the thermodynamics kinetics, crucial information for discovery campaigns. Small-Guanosine Triphosphate Phosphohydrolases (GTPases) regulate a cascade of signaling events, that affect most cellular processes. Their deregulation is linked to several diseases, making them appealing targets. The broad roles small-GTPases in processes recent approval covalent KRas inhibitor as an anticancer agent renewed interest targeting small-GTPase with small molecules.

Language: Английский

Citations

6
Structural Biology of the SARS-CoV-2 replication–transcription complex DOI Creative Commons
Cameron D. Fyfe, Cromarte Rogers, Alexander Matthew Payne

et al.

Crystallography Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 20

Published: March 18, 2025

Language: Английский

Citations

0
The Effect of Chalcogen–Chalcogen Bond Formation in the New Delhi Metallo-β-Lactamase 1 Enzyme to Counteract Antibiotic Resistance DOI
Giada Ciardullo, Mario Prejanò, Angela Parise

et al.

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 24, 2024

New Delhi metallo-β-lactamase 1 (NDM-1) is an enzyme involved in the drug resistance of many bacteria against most widely adopted antibiotics, such as penicillins, cephalosporins, and carbapenems. Consequently, inhibiting NDM-1 swiftly has gained significant interest a strategy to counteract this bacterial defense mechanism, thereby restoring effectiveness antibiotics. Among inhibitors tested enzyme, ebselen (

Language: Английский

Citations

0
Characterization of the Conformational Hotspots of the RNA-Dependent RNA Polymerase Complex Identifies a Unique Structural Malleability of nsp8 DOI

Sowmomita Gharui,

Durba Sengupta, Atanu Das

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 2, 2024

Several antiviral therapeutic approaches have been targeted toward the RNA-dependent RNA polymerase (RdRp) complex that is involved in viral genome replication. In SARS-CoV-2, although RdRp a multiprotein complex, focus has on ligand binding catalytic core (nonstructural protein nsp12), and not functional dynamics. this study, we conformational ensembles of their modulation by presence RNA, performing comprehensive microsecond-scale atomistic simulations apo- RNA-bound complex. We delineate differential impact constituent proteins, such as polymorphisms, dominant segment-specific fluctuations, switch dynamical crosstalk within distinguish signatures nsp7, nsp8, nsp12 apo-state are reduced appear to "prime" for activity. Importantly, identify unique structural malleability nsp8 with high heterogeneity apo state, especially at three sites (Y71 nsp8A, D52 A66 nsp8B). Our work highlights implications polymorphism structures reveals possibilities development allosteric inhibitors.

Language: Английский

Citations

0