Side‐chain control of folding of the homologous α‐, β‐, and γ‐peptides into “mixed” helices (β‐helices)

Abstract

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.

Conformation of gramicidin A in Triton X‐100 micelles from CD and FTIR data: a clean example of antiparallel double β5.6 helix formation

“…The physicochemical principles of channel selectivity, ion–water channel interactions, and some kind of proton transport mechanisms became better understood from the investigations of channel‐mimicking oligopeptides. The channel‐forming polypeptides with β‐structural motif are currently the objects of active study, in particular, with respect to their insertion and folding within the membrane . However, the mechanisms of peptide‐membrane interaction and the folding of β‐structural peptides remain rather obscure because of pronounced structural polymorphism of such peptides.…”

Fundamental Chemical and Structural Principles

“…In particular, in apolar environments, these helices are very stable [120]. Interestingly, such helices show a periodicity of dimer units, that is, the torsion angles of every second amino acid constituent have the same values.…”

Homooligomeric β3(R)‐valine peptides: Transformation between C14 and C12 helical structures induced by a guest Aib residue

“…The explosive development of the field of b and c-peptides, following the seminal work of the groups of Seebach [1,2] and Gellman [3,4] in the mid 1990s, has resulted in the characterization of several novel helical structures which have no precedent in the structural chemistry of a-peptides. [5][6][7][8][9][10] The two most widely studied b-peptide helices are the 12-helix and 14-helix which differ in the nature of their hydrogen bond directionality. [11][12][13] In the b-peptide 12-helix the hydrogen bonding is of the type C 5 O(i) .…”

“…. .. NH(i12) resulting in a 12-atom hydrogen bonded ring (C 12 -pseudocycle), a structure which can be formally viewed as a backbone expanded analogue of the peptide 3 10 -helix extensively characterized in a-peptides, most notably those containing the conformationally constrained a-aminoisobutyryl residue (Aib). [14][15][16] In con-trast, hydrogen bonds run in the opposite direction in the C 14 -helix and are of the type NH(i) .…”