Protein-protein interfaces from cytochrome c oxidase I evolve faster than nonbinding surfaces, yet negative selection is the driving force.
Bottom Line: Herein, using evolutionary data in combination with structural information of COX, we show that failing to discern the effects of interaction from other structural and functional effects can lead to deceptive conclusions such as the "optimizing hypothesis." Once spurious factors have been accounted for, data analysis shows that mtDNA-encoded residues engaged in contacts are, in general, more constrained than their noncontact counterparts.This differential behavior cannot be explained on the basis of predicted thermodynamic stability, as interactions between mtDNA-encoded subunits contribute more weakly to the complex stability than those interactions between subunits encoded by different genomes.Therefore, the higher conservation observed among mtDNA-encoded residues involved in intragenome interactions is likely due to factors other than structural stability.
Affiliation: Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Spain firstname.lastname@example.org.Show MeSH
Mentions: In an attempt to get further insight into the particular forces imposing such exceptionally high degree of conservation among Exposed Noncontact COX I residues (particularly within the Noninterface subset), we assessed the effect of in silico alanine scanning mutagenesis on the stability of the complex. Although the mean ΔΔG for Exposed Noncontact COX I residues (1.64 kJ/mol) was significantly higher than those values from COX II (1.20 kJ/mol) and COX III (1.16 kJ/mol), P values 0.015 and 0.008, respectively, the contribution of COX I Exposed Noncontact residues to the whole thermodynamic stability of the holoenzyme can hardly be invoked as a reason for their high degree of conservation, as it is evident from figure 6. For each mtDNA-encoded protein, the Contact and Exposed Noncontact subsets were employed to compute their ΣdN values, which were plotted against their corresponding ΔΔG mean values (fig. 6). We found a significant negative correlation between these two variables (P value = 0.035), indicating that those substitutions that tend to be more destabilizing are also more constrained, which is in line with our previous observations that thermodynamic stability plays a relevant role in the evolvability of mtDNA-encoded proteins (Aledo et al. 2012). However, the COX I Exposed Noncontact group showed up as an outlier. In this sense, for a ΔΔG of 1.64 kJ/mol (the mean value computed for COX I Exposed Noncontact residues) the expected ΣdN should be higher than twice the observed ΣdN (fig. 6). In other words, whatever the constraining forces may be, they seem to be unrelated to structural stability.Fig. 6.—
Affiliation: Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Spain email@example.com.