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Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SA...

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Autores principales: Ose, Nicholas J., Campitelli, Paul, Modi, Tushar, Can Kazan, I., Kumar, Sudhir, Banu Ozkan, S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515954/
https://www.ncbi.nlm.nih.gov/pubmed/37745560
http://dx.doi.org/10.1101/2023.09.14.557827
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author Ose, Nicholas J.
Campitelli, Paul
Modi, Tushar
Can Kazan, I.
Kumar, Sudhir
Banu Ozkan, S.
author_facet Ose, Nicholas J.
Campitelli, Paul
Modi, Tushar
Can Kazan, I.
Kumar, Sudhir
Banu Ozkan, S.
author_sort Ose, Nicholas J.
collection PubMed
description We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of S protein compared to the closed form. In particular, the CAP sites control the dynamics binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly compensatory variants. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.
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spelling pubmed-105159542023-09-23 Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics Ose, Nicholas J. Campitelli, Paul Modi, Tushar Can Kazan, I. Kumar, Sudhir Banu Ozkan, S. bioRxiv Article We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of S protein compared to the closed form. In particular, the CAP sites control the dynamics binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly compensatory variants. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding. Cold Spring Harbor Laboratory 2023-09-15 /pmc/articles/PMC10515954/ /pubmed/37745560 http://dx.doi.org/10.1101/2023.09.14.557827 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Ose, Nicholas J.
Campitelli, Paul
Modi, Tushar
Can Kazan, I.
Kumar, Sudhir
Banu Ozkan, S.
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
title Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
title_full Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
title_fullStr Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
title_full_unstemmed Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
title_short Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
title_sort some mechanistic underpinnings of molecular adaptations of sars-cov-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515954/
https://www.ncbi.nlm.nih.gov/pubmed/37745560
http://dx.doi.org/10.1101/2023.09.14.557827
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