Alpha Helices Are More Robust to Mutations than Beta Strands
Fig 5
The effect of secondary structure on robustness and pathogenicity of point mutations.
A) Point mutations in experimentally determined structures are significantly less likely to change secondary structure in helices than in strands. (On all panels “*” represents significance below 0.05 and “**” significance below 0.005, controlled for false discovery rate with the Benjamini-Hochberg method, error bars represent 95% confidence intervals.) B) The frequency of pathogenic mutants in conservative mutations that do not result in a change in secondary structure, and in secondary structure breaking mutations. Mutants were grouped according to the RSA of the wild type. Mutations that are predicted to break secondary structure are significantly more pathogenic than the ones that do not change secondary structure, particularly in the case of buried residues. C) Mutations with the same PolyPhen-2 (PP2) score are more likely to be pathogenic if they are predicted to change secondary structure, indicating that information on secondary structure can be used to improve pathogenicity prediction tools The numbers of mutations are 33492, 9953, 9082, 13369 for the PP2 score ranges 0–0.49, 0.5–0.89, 0.9–0.99, 0.99–1.0, respectively. D) Mutations that cause disease are significantly more destabilizing (have a larger effect on the free energy of folding) than neutral mutations in the RSA bins lower than 0.4. E) The higher pathogenicity of mutations that break secondary structure is probably caused by their stronger destabilizing effect on protein structure: the difference between secondary structure changing and non-changing mutations is highly significant in all RSA bins.