High-resolution structures of a heterochiral coiled coil

Abstract

Interactions between polypeptide chains containing amino acid residues with opposite absolute configurations have long been a source of interest and speculation, but there is very little structural information for such heterochiral associations. The need to address this lacuna has grown in recent years because of increasing interest in the use of peptides generated from D amino acids (D peptides) as specific ligands for natural proteins, e.g., to inhibit deleterious proteinprotein interactions. Coiled-coil interactions, between or among α-helices, represent the most common tertiary and quaternary packing motif in proteins. Heterochiral coiled-coil interactions were predicted over 50 years ago by Crick, and limited experimental data obtained in solution suggest that such interactions can indeed occur. To address the dearth of atomic-level structural characterization of heterochiral helix pairings, we report two independent crystal structures that elucidate coiled-coil packing between L-and D-peptide helices. Both structures resulted from racemic crystallization of a peptide corresponding to the transmembrane segment of the influenza M2 protein. Networks of canonical knobs-into-holes side-chain packing interactions are observed at each helical interface. However, the underlying patterns for these heterochiral coiled coils seem to deviate from the heptad sequence repeat that is characteristic of most homochiral analogs, with an apparent preference for a hendecad repeat pattern.D peptides | transmembrane peptides | racemic crystallization | racemic detergent | coiled coil P olypeptides comprising D-amino acid residues have been sources of growing interest for biological applications, often for functions that depend on recognition by specific natural proteins (1-3). D peptides offer identical versatility in terms of conformation and side-chain functionality relative to conventional peptides (composed of L-amino acid residues), but D peptides are impervious to the action of proteolytic enzymes, which should improve pharmacokinetic properties in vivo relative to those of conventional peptides. The engineering of D peptides to display defined protein-binding preferences is hindered, however, by the dearth of experimental information available for such complexes. Structural principles that are well-known to govern interactions between two L-polypeptide chains are not directly extensible to pairings between peptides of opposite chirality. Favorable heterochiral interactions (between L-and D peptides) that are analogous to homochiral associations between L peptides were postulated decades ago on the basis of geometrical considerations (4, 5). In a 1953 analysis of structural parameters governing coiled-coil formation between right-handed α-helices formed from L peptides, for example, Crick suggested that analogous assemblies should be accessible to pairs of right-and left-handed helices (4). In the same year, Pauling and Corey postulated that heterochiral peptide mixtures could form "rippled" β-sheet assemblies with backbo...

Total Chemical Synthesis of Aureocin A53, Lacticin Q and Their Enantiomeric Counterparts

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Parallel Homochiral and Anti‐Parallel Heterochiral Hydrogen‐Bonding Interfaces in Multi‐Helical Abiotic Foldamers

“…Differences from peptide helical bundles should be noted: in peptides, bundling is mostly known between α‐helices of identical handedness which, to best match at their binding interfaces, generally coil around one another. Studies on heterochiral peptide helix bundling and in particular some recent work by Gellman et al., show that homochiral and heterochiral peptide helix interfaces are not equivalent, notably because coil‐coiling is not conducive of better complementarity in heterochiral bundles. In contrast, the rigidity of the aromatic helices hampers coiling, at least over short distances, and strictly parallel arrangements form when mediated by turn units, such as T1 and T2 .…”

Parallele homochirale und antiparallele heterochirale Wasserstoffbrücken‐Interaktionsflächen in multihelikalen abiotischen Foldameren

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