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Evaluation of biologically relevant short alpha-helices stabilized by a main-chain hydrogen-bond surrogate.

ABSTRACT: We previously reported the design and synthesis of a new class of artificial alpha-helices in which an N-terminal main-chain hydrogen bond is replaced by a carbon-carbon bond derived from a ring-closing metathesis reaction [Chapman, R. N.; Dimartino, G.; Arora, P. S. J. Am. Chem. Soc. 2004, 126, 12252-12253]. Our initial study utilized an alanine-rich sequence; in the present manuscript we evaluate the potential of this method for the synthesis of very short (10 residues) alpha-helices representing two different biologically relevant alpha-helical domains. We extensively characterized these two sets of artificial helices by NMR and circular dichroism spectroscopies and find that the hydrogen-bond surrogate approach can afford well-defined short alpha-helical structures from sequences that do not spontaneously form alpha-helical conformations.

SUBMITTER: Wang D

PROVIDER: S-EPMC1828873 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Evaluation of biologically relevant short alpha-helices stabilized by a main-chain hydrogen-bond surrogate.

Wang Deyun D Chen Kang K Kulp Iii John L JL Arora Paramjit S PS

Journal of the American Chemical Society 20060701 28

We previously reported the design and synthesis of a new class of artificial alpha-helices in which an N-terminal main-chain hydrogen bond is replaced by a carbon-carbon bond derived from a ring-closing metathesis reaction [Chapman, R. N.; Dimartino, G.; Arora, P. S. J. Am. Chem. Soc. 2004, 126, 12252-12253]. Our initial study utilized an alanine-rich sequence; in the present manuscript we evaluate the potential of this method for the synthesis of very short (10 residues) alpha-helices represent ...[more]

PMID: 16834399

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Project description:Alpha-helices constitute the largest class of protein secondary structures and play a major role in mediating protein-protein interactions. Development of stable mimics of short alpha-helices would be invaluable for inhibition of protein-protein interactions. This Account describes our efforts in developing a general approach for constraining short peptides in alpha-helical conformations by a main-chain hydrogen bond surrogate (HBS) strategy. The HBS alpha-helices feature a carbon-carbon bond derived from a ring-closing metathesis reaction in place of an N-terminal intramolecular hydrogen bond between the peptide i and i + 4 residues. Our approach is centered on the helix-coil transition theory in peptides, which suggests that the energetically demanding organization of three consecutive amino acids into the helical orientation inherently limits the stability of short alpha-helices. The HBS method affords preorganized alpha-turns to overcome this intrinsic nucleation barrier and initiate helix formation. The HBS approach is an attractive strategy for generation of ligands for protein receptors because placement of the cross-link on the inside of the helix does not block solvent-exposed molecular recognition surfaces of the molecule. Our metathesis-based synthetic strategy utilizes standard Fmoc solid phase peptide synthesis methodology, resins, and reagents and provides HBS helices in sufficient amounts for subsequent biophysical and biological analyses. Extensive conformational analysis of HBS alpha-helices with 2D NMR, circular dichroism spectroscopies and X-ray crystallography confirms the alpha-helical structure in these compounds. The crystal structure indicates that all i and i + 4 C=O and NH hydrogen-bonding partners fall within distances and angles expected for a fully hydrogen-bonded alpha-helix. The backbone conformation of HBS alpha-helix in the crystal structure superimposes with an rms difference of 0.75 A onto the backbone conformation of a model alpha-helix. Significantly, the backbone torsion angles for the HBS helix residues fall within the range expected for a canonical alpha-helix. Thermal and chemical denaturation studies suggest that the HBS approach provides exceptionally stable alpha-helices from a variety of short sequences, which retain their helical conformation in aqueous buffers at exceptionally high temperatures. The high degree of thermal stability observed for HBS helices is consistent with the theoretical predictions for a nucleated helix. The HBS approach was devised to afford internally constrained helices so that the molecular recognition surface of the helix and its protein binding properties are not compromised by the constraining moiety. Notably, our preliminary studies illustrate that HBS helices can target their expected protein receptors with high affinity.

Dataset Information

Evaluation of biologically relevant short alpha-helices stabilized by a main-chain hydrogen-bond surrogate.

Publications

Evaluation of biologically relevant short alpha-helices stabilized by a main-chain hydrogen-bond surrogate.

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