Helix packing motif common to the crystal structures of two undecapeptides containing dehydrophenylalanine residues: implications for the de novo design of helical bundle super secondary structural modules

Abstract

De novo designed peptide based super secondary structures are expected to provide scaffolds for the incorporation of functional sites as in proteins. Self-association of peptide helices of similar screw sense, mediated by weak interactions, has been probed by the crystal structure determination of two closely related peptides: Ac-Gly¹-Ala²-ΔPhe³-Leu⁴-Val⁵-ΔPhe⁶-Leu⁷-Val⁸-ΔPhe⁹-Ala¹⁰-Gly¹¹-NH₂ (I) and Ac-Gly¹-Ala²-ΔPhe³-Leu⁴-Ala⁵-ΔPhe⁶-Leu⁷-Ala⁸-ΔPhe⁹-Ala¹⁰-Gly¹¹-NH₂ (II). The crystal structures determined to atomic resolution and refined to R factors 8.12 and 4.01%, respectively, reveal right-handed 3₁₀-helical conformations for both peptides. CD has also revealed the preferential formation of right-handed 3₁₀-helical conformations for both molecules. Our aim was to critically analyze the packing of the helices in the solid state with a view to elicit clues for the design of super secondary structural motifs such as two, three, and four helical bundles based on helix-helix interactions. An important finding is that a packing motif could be identified common to both the structures, in which a given peptide helix is surrounded by six other helices reminiscent of transmembrane seven helical bundles. The outer helices are oriented either parallel or antiparallel to the central helix. The helices interact laterally through a combination of N-H ^... O, C-H ^... O, and C-H ^... π hydrogen bonds. Layers of interacting leucine residues are seen in both peptide crystal structures. The packing of the peptide helices in the solid state appears to provide valuable leads for the design of super secondary structural modules such as two, three, or four helix bundles by connecting adjacent antiparallel helices through suitable linkers such as tetraglycine segments