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

The Conformational Space of the SARS-CoV-2 Main Protease Active Site Loops is Determined by Ligand Binding and Interprotomer Allostery DOI Creative Commons
Ethan Lee, Sarah Rauscher

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Abstract The main protease (M pro ) of SARS-CoV-2 is essential for viral replication and is, therefore, an important drug target. Here, we investigate two flexible loops in M that play a role catalysis. Using all-atom molecular dynamics simulations, analyze the structural ensemble apo state substrate-bound state. We find can adopt open, intermediate (partly open) closed conformations solution, which differs from partially observed crystal structures . When are or states, catalytic residues more likely to be close proximity, crucial Additionally, substrate binding one protomer homodimer increases fre-quency states bound protomer, while also affecting propensity protomer’s loops. dynamic network analysis, identify multiple allosteric pathways connecting active sites homodimer. Common these hotspot involving N-terminus, critical region comprises part pocket. Taken together, results our simulation study provide detailed insight into relationships between prime target COVID-19.

Language: Английский

Citations

0
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.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 15, 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 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 S 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

1
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Open Access
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

Published: April 3, 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 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 S 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

0
SARS-CoV-2 3CLPro Dihedral Angles Reveal Allosteric Signaling DOI Creative Commons
Daniel J. Evans,

Samreen Sheraz,

Albert Y. Lau

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 22, 2024

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-of-the-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 dihedrals angles transmitting signals.

Language: Английский

Citations

0
The Conformational Space of the SARS-CoV-2 Main Protease Active Site Loops Is Determined by Ligand Binding and Interprotomer Allostery DOI
Ethan Lee, Sarah Rauscher

Biochemistry, Journal Year: 2024, Volume and Issue: 64(1), P. 32 - 46

Published: Nov. 8, 2024

The main protease (M

Language: Английский

Citations

0
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Open Access
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

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 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 S 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 compensatory variants. Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

0
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

Citations

0