INTERACTIONS BETWEEN HYDROPHOBIC SIDE-CHAINS WITHIN ALPHA-HELICES

The thermodynamic basis of helix stability in peptides and proteins is a topic of considerable interest. Accordingly, we have computed the i nteractions between side chains of all hydrophobic residue pairs and s elected triples in a model helix, using Boltzmann-weighted exhaustive modeling. Specifically, all possible pairs from the set Ala, Cys, His, Ile, Leu, Met, Phe, Trp, Tyr, and Val were modeled at spacings of (i, i + 2), (i, i + 3), and (i, i + 4) in the central turn of a model pol y-alanyl alpha-helix. Significant interactions -both stabilizing and d estabilizing- were found to occur at spacings of (i, i + 3) and (i, i + 4), particularly in side chains with rings (i.e., Phe, Tyr, Trp, and His). In addition, modeling of leucine triples in a helix showed that the free energy can exceed the sum of pairwise interactions in certai n cases. Our calculated interaction values both rationalize recent exp erimental data and provide previously unavailable estimates of the con stituent energies and entropies of interaction.