Abstract
An increasing number of experimental and theoretical studies have demonstrated the importance of the 3~10~‐helix/α‐helix/coil equilibrium for the structure and folding of peptides and proteins. One way to perturb this equilibrium is to introduce side‐chain interactions that stabilize or destabilize one helix. For example, an attractive i, i + 4 interaction, present only in the α‐helix, will favor the α‐helix over 3~10~, while an i, i + 4 repulsion will favor the 3~10~‐helix over α. To quantify the 3~10~/α/coil equilibrium, it is essential to use a helix/coil theory that considers the stability of every possible conformation of a peptide. We have previously developed models for the 3~10~‐helix/coil and 3~10~‐helix/α‐helix/coil equilibria. Here we extend this work by adding i, i + 3 and i, i + 4 side‐chain interaction energies to the models. The theory is based on classifying residues into α‐helical, 3~10~‐helical, or nonhelical (coil) conformations. Statistical weights are assigned to residues in a helical conformation with an associated helical hydrogen bond, a helical conformation with no hydrogen bond, an N‐cap position, a C‐cap position, or the reference coil conformation plus i, i + 3 and i, i + 4 side‐chain interactions. This work may provide a framework for quantitatively rationalizing experimental work on isolated 3~10~‐helices and mixed 3~10~‐/α‐helices and for predicting the locations and stabilities of these structures in peptides and proteins. We conclude that strong i, i + 4 side‐chain interactions favor α‐helix formation, while the 3~10~‐helix population is maximized when weaker i, i + 4 side‐chain interactions are present.