Daptomycin is a 13-residue cyclic lipopeptide with Ca 2ϩ -dependent bactericidal activity against a variety of high-risk pathogens. Ring closure in daptomycin is via an ester linkage between the side chain of-free daptomycin is reported to lack a well-defined conformation (D. Jung, A. Rozek, M. Okron, and R. E. W. Hancock, Chemistry & Biology, 2004, Vol. 11, pp. 949-957) or is suggested to populate an alternate conformation (L.-J. Ball, C. M. Goult, J. A. Donarski, J. Micklefield, and V. Ramesh, Organic & Biomolecular Chemistry, 2004, Vol. 2, pp. 1872-1878 Contract grant sponsor: CUBIST Pharmaceuticals and NIH Contract grant number: GM27616 (NIH) *We dedicate this article to the memory of Murray Goodman, a bigger-than-life peptide chemist. He pursued the science of peptide design and synthesis, structure determination, and biological activity with passion. He showed by example how warmth and scientific zeal are contagious traits that engender international liaisons in the pursuit of common goals. He will be sorely missed.

The experiments described here explore the role of local sequence in the folding of cellular retinoic acid binding protein I (CRABP I). This is a 136-residue, 10-stranded, antiparallel beta-barrel protein with seven beta-hairpins and is a member of the intracellular lipid binding protein (iLBP) family. The relative roles of local and global sequence information in governing the folding of this class of proteins are not well-understood. In question is whether the beta-turns are locally defined by short-range interactions within their sequences, and are thus able to play an active role in reducing the conformational space available to the folding chain, or whether the turns are passive, relying upon global forces to form. Short (six- and seven-residue) peptides corresponding to the seven CRABP I turns were analyzed by circular dichroism and NMR for their tendencies to take up the conformations they adopt in the context of the native protein. The results indicate that two of the peptides, encompassing turns III and IV in CRABP I, have a strong intrinsic bias to form native turns. Intriguingly, these turns are on linked hairpins in CRABP I and represent the best-conserved turns in the iLBP family. These results suggest that local sequence may play an important role in narrowing the conformational ensemble of CRABP I during folding.

This paper provides an introduction to fundamental conformational states of polypeptides in the beta-region of phi,psi space, in which the backbone is extended near to its maximal length, and to more complex architectures in which extended segments are linked by turns and loops. There are several variants on these conformations, and they comprise versatile scaffolds for presentation of side chains and backbone amides for molecular recognition and designed catalysts. In addition, the geometry of these fundamental folds can be readily mimicked in peptidomimetics.

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In our effort to understand the structural requirements for the antimicrobial activity of cecropin A (CA) and melittin (M), we synthesized the normal, enantio, retro and retroenantio hybrid analogs; we related activity to their sequence, chirality, amide bond direction (helix dipole) and end group charges. To compare the effect of the end groups, each of these analogs was synthesized both with an acid and an amide C‐terminus and also with and without an Nα‐acetyl N‐terminus. The all‐l‐ and all‐d‐enantiomers of several cecropin‐melittin hybrids were previously found to be equally potent against several bacterial species, and no chiral effect was observed. This general rule has now been confirmed and extended. However, two exceptions have been found. All‐l‐CA(1‐13)M(1‐13) acid was 5 times and 9 times less potent than the all‐d‐analog, respectively, toward Gram‐positive Staphylococcus aureus and Gram‐negative Pseudomonas aeruginosa. A11‐l‐CA(1‐7)M(2‐9) acid was 5 times and 14 times less active against S. aureus and P. aeruginosa, respectively, than its all‐d acid isomer. The corresponding d‐ and l‐retro analogs differed only marginally. A role for proteolytic enzymes has been implicated as a cause for these differences in the activities of l‐ and d‐enantiomers. In all cases, blocking the α‐amine by acetylation had no significant effect on potency. The retro and retroenantio analogs of CA(1‐13)M(1‐13) acid were as potent as their normal and enantio analogs against all the test bacteria. The C‐terminal amides also showed similar potency against four test bacteria. It should be noted that the negative end of the helix dipole of a normal peptide points toward the C‐terminus, whereas it points away in the case of a retro derivative when viewed in the direction of the normal sequence.