Modeling the Relationship between the Capsid Spike Protein Stability and Fitness in ϕX174 Bacteriophage
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Protein function depends on the stable folding or binding of peptide chains, and the extent to which an amino acid substitution disrupts this stability can be a strong predictor of the mutation’s impact on the protein’s function and the organism’s fitness. This study seeks to understand this relationship in bacteriophage ϕX174 using an experimental technique of deep mutational scanning and computationally predicted protein stability.
Results
Analyzing the viability data using a newly developed multistage binomial model confirms that highly destabilizing mutations predict inviability. For single-site variants, the model predicts that ΔΔG of folding greater than ~3 kcal/mol and ΔΔG of binding greater than ~6 kcal/mol cuts the probability of survival by half of the maximum. The maximum probability, even for minimal ΔΔG values, plateaus at around 87%, reflecting the influence of unobserved factors. Fitting of double-site variants data shows similar results. In contrast, a linear regression analysis of viable mutants reveals that the effect of protein stability is too weak to be a reliable predictor of fitness.
Conclusion
In this study, we introduce a novel modeling technique to explore the relationship between protein stability and survival outcomes. While large destabilization often indicates inviability, most destabilizing mutations exert only small to moderate effects and do not reliably predict survival. Although protein stability is a crucial biophysical property influencing biological systems, it represents just one of multiple factors that contribute to fitness and survival.
