Analyzing enzyme dynamics

Previous simulation studies have suggested that structural dynamics and protein motion play an important role in enzyme catalysis, but these results are difficult to verify experimentally. R. August Estabrook et al. have developed a predictive approach to guide the direct experimental testing of how enzyme dynamics impact catalysis. Their method highlights specific amino acid pairs likely to be essential for catalysis by identifying those that show both dynamic and evolutionary couplings. The authors combined two analytical methods, each of which measures a type of covariation between amino acid positions. Molecular dynamics simulations reveal protein regions with correlated motions, while statistical coevolution analysis finds protein segments that are highly coevolved or coupled. The authors demonstrated their approach on the DNA methyltranferase M.HhaI and found that the coevolved amino acid residues of M.HhaI with highly correlated motions in the same direction (in terms of backbone -carbon motion) were within van der Waals contact. These interactions are believed to be critical structural elements for maintaining enzymatic functions. Coevolved residues moving in opposite directions (anticorrelated motion) were found to lie on opposing sides of the enzyme active site and may mediate active-site compressions.