Correlation between calculated local stability and hydrogen exchange rates in proteins

The attempt is made to find new correlations between local structural characteristics of proteins and the hydrogen exchange rates of their individual main-chain amides, and to relate such correlations to possible mechanisms of hydrogen exchange. It is found that in bovine pancreatic trypsin inhibitor (BPTI) the surface area buried by a particular residue and its neighbors correlates with the exchange rate of the main-chain amide of that residue. As the area buried by a particular fragment can be associated with the stabilization of the protein structure by this fragment, the correlation suggests a role for the energetics of the local unfolding in the mechanism of hydrogen exchange. Calculations based on the assumption that the exchange mechanism involves local unfolding lead to quantitative agreement between the calculated and experimentally measured exchange rates for 80% of the amides of BPTI that are buried or hydrogen bonded to the main-chain or to internal water molecules. The same degree of correlation is found between the calculated exchange rates and partial exchange data for ribonuclease S, hen lysozyme and cytochrome c. A similarly strong correlation is found between calculated exchange rates and the exchange rates of ribonuclease A determined by neutron diffraction in the crystal. The criteria of correlation are, however, less stringent in this case because of the experimental errors, which are larger than for solution data. It is suggested that the observed correlation be used for predictions of hydrogen exchange rates in proteins.