A new statistical thermodynamic formalism has been developed in order to describe the equilibrium folding pathway of proteins. The resulting formalism allows calculation of the probabilities that individual amino acids will be in a native or native-like conformation for any degree of folding of the molecule. The residue probabilities are defined by the probability distribution of conformational states and can be used to calculate experimental quantities like native state hydrogen exchange protection factors. A combinatorial algorithm aimed at generating a large ensemble of conformational states (104-106) using the native structure as a template has been developed. The Gibbs energy and corresponding probability of each conformational state is estimated by using a previously described structural parametrization of the energetics. The approach has been applied to five proteins: hen egg white lysozyme, equine lysozyme, BPTI, staphylococcal nuclease, and turkey ovomucoid third domain. The validity of the approach has been tested by comparing predicted and experimental hydrogen exchange protection factors. The good agreement between experimental and predicted values permits a close examination of the nature of the equilibrium folding intermediates existing under conditions of maximal stability of the native state.
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