A new study indicates that mutations in the spike proteins of SARS-CoV-2 are selecting for amino acid changes that result in a more stable protein than expected by chance.
Protein folding is governed by the thermodynamic principle of Gibbs Free Energy (ΔΔG), which states that the amino acid sequence of a protein determines its native structure. This native structure has the minimum ΔΔG.
Prediction of the changes in ΔΔG are routinely used in protein engineering and design for optimization of enzymes or stabilisation of protein complexes.
A team of researchers at the Department of Medical Physics and Biomedical Engineering at the UCL did a study on the ΔΔG values of the general population of mutations and the variants. They calculated the ΔΔG for every possible missense mutation in the S-protein, which amounted to a total of 19,440 mutations.
This information was subsequently described as the "background" mutation rate.
Taking their research one step further, the researchers compared the background mutational distribution between VOCs and SARS-CoV-2 “Variants of Interest (VOIs).” Both SARS-CoV-2 VOIs and VOCs were found to exhibit significantly lower ΔΔG values as compared to the bulk population, thereby indicating that these variants likely have been evolutionarily selected for stabilizing or non-destabilizing mutations.
Notably, none of the VOCs were found to contain mutations that were strongly destabilizing, which was defined as ΔΔG values greater than 2.5 Kcal/mol. Overall, the researchers concluded that a statistical enrichment exists for SARS-CoV-2 mutations that stabilize the S protein as compared to the background.
Conclusion: This work highlights that mutations with a stabilising effect on the SARS-CoV-2 spike protein are one of the key drivers of evolution of the virus, and contributing to the increased transmissibility of emerging variants. That variants are more stable than expected by chance shows that evolution is favouring mutations with a stabilising effect, and it may be that mutations that destabilise a protein but have other influences on protein structure, such as K417N, which alters ACE2 binding affinity, are offset or preceded by mutations that stabilise the structure.
Protein folding is governed by the thermodynamic principle of Gibbs Free Energy (ΔΔG), which states that the amino acid sequence of a protein determines its native structure. This native structure has the minimum ΔΔG.
Prediction of the changes in ΔΔG are routinely used in protein engineering and design for optimization of enzymes or stabilisation of protein complexes.
A team of researchers at the Department of Medical Physics and Biomedical Engineering at the UCL did a study on the ΔΔG values of the general population of mutations and the variants. They calculated the ΔΔG for every possible missense mutation in the S-protein, which amounted to a total of 19,440 mutations.
This information was subsequently described as the "background" mutation rate.
Taking their research one step further, the researchers compared the background mutational distribution between VOCs and SARS-CoV-2 “Variants of Interest (VOIs).” Both SARS-CoV-2 VOIs and VOCs were found to exhibit significantly lower ΔΔG values as compared to the bulk population, thereby indicating that these variants likely have been evolutionarily selected for stabilizing or non-destabilizing mutations.
Notably, none of the VOCs were found to contain mutations that were strongly destabilizing, which was defined as ΔΔG values greater than 2.5 Kcal/mol. Overall, the researchers concluded that a statistical enrichment exists for SARS-CoV-2 mutations that stabilize the S protein as compared to the background.
Conclusion: This work highlights that mutations with a stabilising effect on the SARS-CoV-2 spike protein are one of the key drivers of evolution of the virus, and contributing to the increased transmissibility of emerging variants. That variants are more stable than expected by chance shows that evolution is favouring mutations with a stabilising effect, and it may be that mutations that destabilise a protein but have other influences on protein structure, such as K417N, which alters ACE2 binding affinity, are offset or preceded by mutations that stabilise the structure.
