ADDITION OF SIDE-CHAIN INTERACTIONS TO 3(10)-HELIX COIL AND ALPHA-HELIX/3(10)-HELIX/COIL THEORY/

An increasing number of experimental and theoretical studies have demo nstrated the importance of the 3(10)-helix/alpha-helix/coil equilibriu m for the structure and folding of peptides and proteins. One way to p erturb this equilibrium is to introduce side-chain interactions that s tabilize or destabilize one helix. For example, an attractive i, i + 4 interaction present only in the alpha-helix, will favor the alpha-hel ix over 3(10), while an i, i + 4 repulsion will favor the 3(10)-helix over alpha. To quantify the 3(10)/alpha/coil equilibrium, it is essent ial to use a helix/coil theory that considers the stability of every p ossible conformation of a peptide. We have previously developed models for the 3(10)-helix/coil and 3(10)-helix/alpha-helix/coil equilibria. Here we extend this work by adding i, i + 3 and i, i + 4 side-chain i nteraction energies to the models. The theory is based on classifying residues into alpha-helical, 3(10)-helical, or nonhelical (coil) confo rmations. Statistical weights are assigned to residues in a helical co nformation with an associated helical hydrogen bond, a helical conform ation with no hydrogen bond, an N-cap position, a C-cap position, or t he reference coil conformation plus i, i + 3 and i? i + 4 side-chain i nteractions. This work may provide a framework for quantitatively rati onalizing experimental work on isolated 3(10)-helices and mixed 3(10)- /alpha-helices and for predicting the locations and stabilities of the se structures in peptides and proteins. We conclude that strong i, i 4 side-chain interactions favor alpha-helix formation, while the 3(10 )-helix population is maximized when weaker i, i + 4 side-chain intera ctions are present.