LAUSR

The question of whether amino acids critical to protein folding kinetics are evolutionarily conserved has been investigated intensively in the past, but no consensus has yet been reached. Recently, we have demonstrated that the transition state, dictating folding kinetics, is characterized as the state of maximum dynamic cooperativity, i.e., the state of maximum correlations between amino acid contact formations. Here, we investigate the evolutionary conservation of those amino acids contributing significantly to the dynamic cooperativity. We find a strong indication of a new kind of relationship—necessary but not sufficient causality—between the evolutionary conservation and the dynamic cooperativity: larger contributions to the dynamic cooperativity arise from more conserved residues, but not vice versa. This holds for all the protein systems for which long folding simulation trajectories are available. To our knowledge, this is the first systematic demonstration of any kind of evolutionary conservation of amino acids relevant to folding kinetics.