Protein dynamics provide mechanistic insights about the epistatic relationships among highly observed potentially adaptive missense variants

Ose, Nicholas J.; Campitelli, Paul; Patel, Ravi; Ozkan, S. Banu; Kumar, Sudhir

doi:10.1016/j.bpj.2021.11.488

“…Similar cleavage sites have been found in related coronaviruses, including HKU1 and Middle East respiratory syndrome coronavirus (MERS-CoV), which infect humans (Chan et al 2008 : 1;Millet and Whittaker 2014 ;Millet and Whittaker 2015 ), and the acquisition of similar cleavage sites is associated with increased pathogenicity in other viruses such as the influenza virus (Steinhauer 1999 ). Interestingly, however, CAPs do not display such an overwhelming tendency to occur at well-known critical sites within human proteins studied with similar methods (Ose, Campitelli, et al 2022 ), yet mutations at those sites are associated with disease, indicating their critical role in inducing functional change. Therefore, the identified CAPs in the S protein, which are signs of recent evolution, can provide mechanistic insights regarding the molecular adaptation of the virus.…”

Section: Figurementioning

confidence: 63%

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

Ose,

Campitelli,

Modi

et al. 2023

Preprint

Self Cite

0

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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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“…An EpiScore of 1 indicates perfect coupling additivity, and deviations from this value represent non-additive behavior between position pairs and functionally important sites. Prior EpiScore work has shown a difference in EpiScore between the sites of compensatory and non-compensatory mutations, where both yield distributions with peaks around 1, but noncompensatory mutations show higher deviation in their EpiScore distribution (Ose, Campitelli, et al 2022 ).…”

Section: Experimental Results Motivate the Use Of Episcore Within The...mentioning

confidence: 99%

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

Ose,

Campitelli,

Modi

et al. 2024

eLife

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0

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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.

show abstract

“…Similar cleavage sites have been found in related coronaviruses, including HKU1 and Middle East respiratory syndrome coronavirus (MERS-CoV), which infect humans (Chan et al 2008: 1; Millet and Whittaker 2014; Millet and Whittaker 2015), and the acquisition of similar cleavage sites is associated with increased pathogenicity in other viruses such as the influenza virus (Steinhauer 1999). Interestingly, however, CAPs do not display such an overwhelming tendency to occur at well-known critical sites within human proteins studied with similar methods (Ose, Campitelli, et al 2022), yet mutations at those sites are associated with disease, indicating their critical role in inducing functional change. Therefore, the identified CAPs in the S protein, which are signs of recent evolution, can provide mechanistic insights regarding the molecular adaptation of the virus.…”

Section: Resultsmentioning

confidence: 99%

“…An EpiScore of 1 indicates perfect coupling additivity, and deviations from this value represent non-additive behavior between position pairs and functionally important sites. Prior EpiScore work has shown a difference in EpiScore between the sites of compensatory and non-compensatory mutations, where both yield distributions with peaks around 1, but non-compensatory mutations show higher deviation in their EpiScore distribution (Ose, Campitelli, et al 2022).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, however, CAPs do not display such an overwhelming tendency to occur at well-known critical sites within human proteins studied with similar methods (Ose, Campitelli, et al 2022), yet mutations at those sites are associated with disease, indicating their critical role in inducing functional change. Therefore, the identified CAPs in the S protein, which are signs of recent evolution, can provide mechanistic insights regarding the molecular adaptation of the virus.…”

Section: Figure 1 (A)mentioning

confidence: 99%

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

Ose,

Campitelli,

Modi

et al. 2023

Preprint

Self Cite

1

0

View full text Add to dashboard Cite

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.

show abstract

Protein dynamics provide mechanistic insights about the epistatic relationships among highly observed potentially adaptive missense variants

Cited by 5 publications

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

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

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

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

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