Side-chain control of folding of the homologous alpha-, beta-, and gamma-peptides into "mixed" helices (beta-helices).

A systematic analysis of the substituent influence on the formation of the unique secondary structure type of "mixed" helices in the homologous alpha-, beta-, and gamma-peptides was performed on the basis of ab initio molecular orbital theory. Contrary to the common periodic peptide helices, mixed helices have an alternating periodicity and their hydrogen-bonding pattern is similar to those of beta-sheets. They belong, therefore, to the family of beta-helices. It is shown that folding of peptide sequences into mixed helices is energetically preferred over folding into their periodic counterparts in numerous cases. The influence of entropy and solvents on the formation of the various competitive mixed and periodic helix types is discussed. Among the oligomers of the various homologous amino acids, beta-peptides show the highest tendency to form beta-helices. The rules of substituent influence derived from the analysis of a wide variety of backbone substitution patterns might be helpful for a rational design of mixed helix structures, which could be important for mimicking membrane channels. Copyright (c) 2005 Wiley Periodicals, Inc.