Thermodynamic environments in proteins: fundamental determinants of fold specificity.

To investigate the relationship between an amino acid sequence and its corresponding protein fold, a database of thermodynamic stability information was assembled as a function of residue type from 81 nonhomologous proteins. This information was obtained using the COREX algorithm, which computes an ensemble-based description of the native state of proteins. Dissection of the COREX stability constant into its fundamental energetic components resulted in 12 thermodynamic environments describing the tertiary architecture of protein folds. Because of the observation that residue types partitioned unequally between these environments, it was hypothesized that thermodynamic environments contained energetic information that connected sequence to fold. To test the significance of this hypothesis, the thermodynamic stability information was incorporated into a three-dimensional-to-one-dimensional scoring matrix, and simple fold recognition experiments were performed in a manner such that information about the fold target was never included in the scoring. For 60 out of 81 fold targets, the correct sequence for the target scored in the top 5% of 3858 decoy sequences, with Z-scores ranging from 1.76 to 12.23. Furthermore, a scoring matrix assembled from the residues of 40 nonhomologous all-alpha proteins was used to thread sequences against 12 nonhomologous all-beta protein targets. In 10 of 12 cases, sequences known to adopt the native all-beta structure scored in the top 5% of 3858 decoy sequences, with Z-scores ranging from 1.99 to 7.94. These results indicate that energetic information encoded by thermodynamic environments represents a fundamental property of proteins that underlies classifications based on secondary structure.