Building Quantitative Bridges between Dynamics and Sequences of SARS-CoV-2 Main Protease and a Diverse Set of Thirty-Two Proteins DOI
Ahmet Yildirim, Mustafa Tekpinar

Journal of Chemical Information and Modeling, Journal Year: 2022, Volume and Issue: 63(1), P. 9 - 19

Published: Dec. 13, 2022

Proteases are major drug targets for many viral diseases. However, mutations can render several antiprotease drugs inefficient rapidly even though these may not alter protein structures significantly. Understanding relations between quickly mutating residues, protease structures, and the dynamics of proteases is crucial designing potent drugs. Due to this reason, we studied evolutionary information on residues in amino acid sequences SARS-CoV-2 main protease. More precisely, analyzed three dynamical quantities (Schlitter entropy, root-mean-square fluctuations, flexibility index) their relation conservation extracted from multiple sequence alignments We showed that a quantifiable similarity be built sequence-based quantity called Jensen–Shannon those quantities. validated diverse set 32 different proteins, other than believe establishing kinds quantitative bridges will have larger implications all as well proteins.

Language: Английский

MD simulations indicate Omicron P132H of SARS-CoV-2 Mpro is a potential allosteric mutant involved in modulating the dynamics of catalytic site entry loop DOI
Zahoor Ahmad Bhat,

Mohd Muzammil Khan,

Ayyub Rehman

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 262, P. 130077 - 130077

Published: Feb. 10, 2024

Language: Английский

Citations

7
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

eLife, Journal Year: 2024, Volume and Issue: 12

Published: May 7, 2024

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) SARS-CoV-2 S and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

4
Decoding Allosteric Landscapes: Computational Methodologies for Enzyme Modulation and Drug Discovery DOI Creative Commons
Ruidi Zhu, Chengwei Wu, Jinyin Zha

et al.

RSC Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Allosteric regulation is a fundamental mechanism in enzyme function, enabling dynamic modulation of activity through ligand binding at sites distal to the active site. modulators have gained significant attention due their unique advantages, including enhanced specificity, reduced off-target effects, and potential for synergistic interaction with orthosteric agents. However, inherent complexity allosteric mechanisms has posed challenges systematic discovery design modulators. This review discusses recent advancements computational methodologies identifying characterizing enzymes, emphasizing techniques such as molecular dynamics (MD) simulations, sampling methods, normal mode analysis (NMA), evolutionary conservation analysis, machine learning (ML) approaches. Advanced tools like PASSer, AlloReverse, AlphaFold further understanding facilitated selective Case studies on enzymes Sirtuin 6 (SIRT6) MAPK/ERK kinase (MEK) demonstrate practical applications these approaches drug discovery. By integrating predictions experimental validation, this highlights transformative strategies advancing discovery, offering innovative opportunities regulate therapeutic benefits.

Language: Английский

Citations

0
SARS‐CoV‐2 Mpro Dihedral Angles Reveal Allosteric Signaling DOI Open Access
Daniel J. Evans,

Samreen Sheraz,

Albert Y. Lau

et al.

Proteins Structure Function and Bioinformatics, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

ABSTRACT In allosteric proteins, identifying the pathways that signals take from ligand‐binding sites to enzyme active or binding pockets and interfaces remains challenging. This avenue of research is motivated by goals understanding particular macromolecular systems interest creating general methods for their study. An especially important protein subject many investigations in allostery SARS‐CoV‐2 main protease (Mpro), which necessary coronaviral replication. It both an attractive drug target and, due intense it development pharmaceutical compounds, a gauge state art approaches studying inhibition. Here we develop computational method characterizing use study Mpro. We propose role protein's C‐terminal tail modulation warn unintuitive traps can plague studies dihedral angles transmitting signals.

Language: Английский

Citations

0
Protein dynamics provide mechanistic insights about epistasis among common missense polymorphisms DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Ravi Patel

et al.

Biophysical Journal, Journal Year: 2023, Volume and Issue: 122(14), P. 2938 - 2947

Published: Feb. 2, 2023

Language: Английский

Citations

6
Integration of LC/MS, NMR and Molecular Docking for Profiling of Bioactive Diterpenes from Euphorbia mauritanica L. with in Vitro Anti‐SARS‐CoV‐2 Activity DOI

Ahmed F. Essa,

Seham S. El‐Hawary,

Tahia M. Kubacy

et al.

Chemistry & Biodiversity, Journal Year: 2023, Volume and Issue: 20(2)

Published: Jan. 5, 2023

In spite of tremendous efforts exerted in the management COVID-19, absence specific treatments and prevalence delayed long-term complications termed post-COVID syndrome still urged all concerned researchers to develop a potent inhibitor SARS-Cov-2. The hydromethanolic extracts different parts E. mauritanica were vitro screened for anti-SARS-Cov-2 activity. Then, using an integrated strategy LC/MS/MS, molecular networking NMR, chemical profile active extract was determined. To determine optimum target these compounds, docking experiments extract's identified compounds conducted at several viral targets. leaves showed best inhibitory effect with IC50 8.231±0.04 μg/ml. jatrophane diterpenes provisionally annotated as primary metabolites bioactive based on multiplex network, NMR. silico studies revealed potentiality most 3CLpro, where compound 20 binding affinity. Further attention should be paid isolation various from Euphorbia evaluating their effects SARS-Cov-2 its

Language: Английский

Citations

4
Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory DOI
Paul Campitelli, Tushar Modi, S. Banu Ozkan

et al.

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

Published: Aug. 7, 2024

We report a new approach that combines molecular dynamics trajectories with time-dependent linear response theory to compute the time evolution of residue fluctuation responses force perturbations exerted at functional sites. Applying this TEM-1 beta-lactamase, we observe time-resolved profiles allosteric sites active are distinct from those non-allosteric residues. Using Fourier transformations, convert domain frequency and demonstrate space representation perturbation can capture mutational behavior each site when applied deep sequencing data. Furthermore, show classification models built on accurately identify distal positions regulate antibiotic resistance. These findings provide insights into contributions specific residues resistance-encoded in highlight importance identifying mutations, opening avenues for potential characterization additional without extensive computational simulations.

Language: Английский

Citations

1
Potential Self-Peptide Inhibitors of the SARS-CoV-2 Main Protease DOI
Arkadeep Banerjee, Shachi Gosavi

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(4), P. 855 - 865

Published: Jan. 23, 2023

The SARS-CoV-2 main protease (Mpro) plays an essential role in viral replication, cleaving polyproteins into functional proteins. This makes Mpro important drug target. consists of N-terminal catalytic domain and a C-terminal α-helical (MproC). Previous studies have shown that peptides derived from given protein sequence (self-peptides) can affect the folding and, turn, function protein. Since SARS-CoV-1 MproC is known to stabilize its regulate function, we hypothesized MproC-derived self-peptides may modulate Mpro. To test this, studied presence various using coarse-grained structure-based models molecular dynamics simulations. In these simulations one self-peptide, found two self-peptides, α1-helix loop between α4 α5 (loop4), could replace equivalent native sequences structure. Replacement either full-length should, principle, be able perturb albeit through different mechanisms. Some general principles for rational design self-peptide inhibitors emerge: show prefolded are more likely than those which do not possess Additionally, kinetically stable once inserted rarely exchanges with α1-helix, while loop4 easily replaced by loop4, making it less useful modulating function. summary, α1-derived peptide should inhibit

Language: Английский

Citations

3
Wordom update 2: A user-friendly program for the analysis of molecular structures and conformational ensembles DOI Creative Commons
Angelo Felline, Simone Conti, Michele Seeber

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2023, Volume and Issue: 21, P. 1390 - 1402

Published: Jan. 1, 2023

We present the second update of Wordom, a user-friendly and efficient program for manipulation analysis conformational ensembles from molecular simulations. The actual expands some existing modules adds 21 new to 1 published in 2011. can be divided into three sets that: 1) analyze atomic fluctuations structural communication; 2) explore ion-channel dynamics ionic translocation; 3) compute geometrical indices deformation. Set serves correlations motions, find geometrically stable domains, identify dynamically invariant core, changes domain-domain separation mutual orientation, perform wavelet large-scale simulations, process output principal component fluctuations, functional mode analysis, infer regions mechanical rigidity, overall perturbation response scanning. 2 includes specific ion channels, which serve monitor pore radius as well water or fluxes, measure collective motions like receptor twisting tilting angles. Finally, set 3 tools deformations by computing angles, perimeter, area, volume, β-sheet curvature, radial distribution function, center mass. ring perception module is also included, helpful supramolecular self-assemblies. This places Wordom among most suitable, complete, user-friendly, software biomolecular source code relative documentation are available under GNU general public license at http://wordom.sf.net.

Language: Английский

Citations

3
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Nov. 6, 2023

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) SARS-CoV-2 S and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

2