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 acid residues will be in a native or native-like conformation for any given degree of folding of the protein 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 (10(4) to 10(6)) 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 developed structural parametrization of the energetics. The approach has been applied to five different proteins: hen egg-white lysozyme, equine lysozyme, bovine pancreatic trypsin inhibitor, staphylococcal nuclease and turkey ovomucoid third domain. The validity of the approach has been tested by comparing predicted and experimental hydrogen exchange protection factors. It is shown that for the above proteins 76%, 73%, 74%, 78% and 81% of all observed protection factors are predicted correctly. Furthermore, on average, the magnitude of the predicted protection factors, expressed as apparent free energies per residue deviate less than 1 kcal/mol from those obtained experimentally. These results represent the first attempt at predicting both the location and magnitude of hydrogen exchange protection factors from the high-resolution structure of a protein. The good agreement between experimental and predicted values has permitted a close examination of the nature of the equilibrium folding intermediates existing under conditions of maximal stability of the native state.