ALPHA-HELIX CAPPING IN SYNTHETIC MODEL PEPTIDES BY RECIPROCAL SIDE-CHAIN MAIN-CHAIN INTERACTIONS - EVIDENCE FOR AN N-TERMINAL CAPPING BOX

A significant fraction of the amino acids in proteins are alpha helical in conformation. Alpha helices in globular proteins are short, with an average length of about twelve residues, so that residues at the ends of helices make up an important fraction of all helical residues. In the middle of a helix, H-bonds connect the NH and CO groups of each residue to partners four residues along the chain. At the ends of a helix, the H-bond potential of the main chain remains unfulfilled, and helix capping interactions involving bonds from polar side chains to the NH or CO of the backbone have been proposed and detected. In a study of synthetic helical peptides, we have found that the sequence Ser-Glu-Asp-Glu stabilizes the alpha helix in a series of helical peptides with consensus sequences. Following the report by Harper and Rose, which indentifies SerXAaXaaGlu as a member of a class of common motifs at the N termini of alpha helices in proteins that they refer to as ''capping boxes,'' we have reexamined the side chain-main chain interactions in a varient sequence using H-1 NMR, and find that the postulated reciprocal side chain-backbone bonding between the first Ser and last Glu side chains and their peptide NH partners can be resolved. Deletion of two residues N terminal to the Ser-Glu-Asp-Glu sequence in these peptides has no effect on the initiation of helical structure, as defined by two-dimensional (2D) NMR experiments on this variant. Thus the capping box sequence Ser-Glu-Asp-Glu inhibits N terminal fraying of the N terminus of alpha helix in these peptides, and shows the side chain-main chain interactions proposed by Harper and Rose. It thus acts as a helix initiating signal. Since normal alpha helix cannot propagate beyond the N terminus of this structure, the box acts as a termination signal in this direction as well. (C) 1994 Wiley-Liss, Inc.