Evolutionary conservation in protein folding kinetics

The sequence and structural conservation of folding transition states have been predicted on theoretical grounds. Using homologous sequence alignments of proteins previously characterized via coupled mutagenesis/kinetics stud ies, we tested these predictions experimentally. Only one of the six approp riately characterized proteins exhibits a statistically significant correla tion between residues' roles in transition state structure and their evolut ionary conservation. However, a significant correlation is observed between the contributions of individual sequence positions to the transition state structure across a set of homologous proteins. Thus the structure of the f olding transition state ensemble appears to be more highly conserved than t he specific interactions that stabilize it. (C) 2000 Academic Press.