Anticipating future SARS-CoV-2 variants of concern through ab initio quantum mechanical modeling
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Abstract
Evolved SARS-CoV-2 variants are currently challenging the efficacy of first-generation vaccines, largely through the emergence of spike protein mutants. Among these variants, Delta is presently the most concerning. We employ an ab initio quantum mechanical model based on Density Functional Theory to characterize the spike protein Receptor Binding Domain (RBD) interaction with host cells and gain mechanistic insight into SARS-CoV-2 evolution. The approach is illustrated via a detailed investigation of the role of the E484K RBD mutation, a signature mutation of the Beta and Gamma variants. The simulation is employed to: predict the depleting effect of the E484K mutation on binding the RBD with select antibodies; identify residue E484 as a weak link in the original interaction with the human receptor hACE2; and describe SARS-CoV-2 Wuhan strand binding to the bat Rhinolophus macrotis ACE2 as more optimized than the human counterpart. Finally, we predict the hACE2 binding efficacy of a hypothetical E484K mutation added to the Delta variant RBD, identifying a potential future variant of concern. Results can be generalized to other mutations, and provide useful information to complement existing experimental datasets of the interaction between randomly generated libraries of hACE2 and viral spike mutants. We argue that ab initio modeling is at the point of being aptly employed to inform and predict events pertinent to viral and general evolution.
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SciScore for 10.1101/2021.11.25.470044: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Structure relaxations are performed by optimizing the crystal geometry with the OpenMM package using the AMBER FF14SB force field [28]. OpenMMsuggested: (OpenMM, RRID:SCR_000436)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:On the other side, the abundance of data for SARS-CoV-2 has provided an opportunity to test and validate the potentials and limitations of ab initio …
SciScore for 10.1101/2021.11.25.470044: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Structure relaxations are performed by optimizing the crystal geometry with the OpenMM package using the AMBER FF14SB force field [28]. OpenMMsuggested: (OpenMM, RRID:SCR_000436)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:On the other side, the abundance of data for SARS-CoV-2 has provided an opportunity to test and validate the potentials and limitations of ab initio modeling. This, in conjunction with the maturity of large-scale quantum mechanical calculations, represents a unique opportunity to employ full QM calculations to uncover the interaction mechanisms which would be difficult or impossible to investigate otherwise. We show that ab initio modeling provides insights useful for comparison with experimental data, supporting its capability to offer predictive power for inter-molecular interactions of biological relevance. Research paradigms on large biomolecules investigation, in various domains, can now effectively include QM data. Model limitations: The model, despite its first-principles origin, is based on assumptions. First, the quantities we are investigating, while representing the binding energy, do not directly manifest experimental results. A closely-related quantity may be the off-rate dissociation constant, that can be inversely proportional to the structures’ stability. However, to correctly evaluate such terms, the systems’ free energies must be considered, which would require dynamic structural investigations. Additionally, the mutated structures are based on reference structures whose 3D conformation may in principle be altered by a given mutation. Therefore, in the absence of confirmed crystal structures, these structures can only be interpreted as virtual best guesses. ...
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Results from scite Reference Check: We found no unreliable references.
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