Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro
Abstract
:1. Introduction
2. Methods
2.1. Spike Protein Structures
- Human monoclonal nAbs generated in response to SARS-CoV-2 infection;
- nAbs targeting the spike protein;
- nAbs/spike protein complexes available in the PDB, with X-ray structure of resolution ≤ 3.2 Å.
2.2. Spike Protein Stability
2.3. Spike Protein/ACE2 Binding Affinity
2.4. Spike Protein/nAb Binding Affinity
2.5. SARS-CoV-2 Fitness
- Mutations i that strongly destabilize the spike protein () or its binding to ACE2 (), or that stabilize its binding with nAbs () have a fitness close to zero.
- Mutations that stabilize the spike protein () or its binding to ACE2 (), or that destabilize its binding to nAbs () have an evolutionary advantage and a fitness higher than one.
- To avoid excessively high fitness values, we cut the exponential growth of the -functions for , with chosen to be , similarly to what has been proposed in [42].
- The folding free energy changes predicted by PoPMuSiC have been shown to be biased towards destabilizing mutations [43,44]. To correct for this effect, the parameter was chosen to be equal to 0.5. The changes in binding free energy predicted by BeAtMuSiC have an analogous bias, as they are constructed from PoPMuSiC scores. Following the BeAtMuSiC construction detailed in [35], a bias in the PoPMuSiC energy value of 0.5 kcal/mol results in a bias in the BeAtMuSiC energy value of 0.19 kcal/mol. We thus fixed and .
- We set by definition the fitness value of the wild-type equal to one: .
3. Results
3.1. Computational Pipeline
3.2. Spike Protein Stability and SARS-Cov-2 Transmissibility
3.3. Spike Protein/ACE2 Binding Affinity and SARS-CoV-2 Infectivity
3.4. Spike Protein/nAb Binding Affinity and Immune Escape
3.5. Immune Escape from Polyclonal Human Sera
3.6. Overall Variant Fitness, Transmissibility, Infectivity and Immune Escape
3.7. Viral Evolution and Overall Fitness
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variants | Resistance to nAbs | |
---|---|---|
S349A | 35% | 1.1 |
G446A | 37% | 1.4 |
G447A | 41% | 1.6 |
N448A | 26% | 1.5 |
E484A | 44% | 1.1 |
Variants | Occurrences | ||||
---|---|---|---|---|---|
D614G | 96% | 3.7 | 1.0 | 1.0 | 3.7 |
A222V | 19% | 2.0 | 1.0 | 1.0 | 2.0 |
P681H | 19% | 1.6 | 1.0 | 1.0 | 1.6 |
N501Y | 18% | 2.1 | 1.4 | 1.0 | 2.9 |
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Pucci, F.; Rooman, M. Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro. Viruses 2021, 13, 935. https://doi.org/10.3390/v13050935
Pucci F, Rooman M. Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro. Viruses. 2021; 13(5):935. https://doi.org/10.3390/v13050935
Chicago/Turabian StylePucci, Fabrizio, and Marianne Rooman. 2021. "Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro" Viruses 13, no. 5: 935. https://doi.org/10.3390/v13050935
APA StylePucci, F., & Rooman, M. (2021). Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro. Viruses, 13(5), 935. https://doi.org/10.3390/v13050935