Dataset Information

Prediction of Xaa-Pro peptide bond conformation from sequence and chemical shifts.

ABSTRACT: We present a program, named Promega, to predict the Xaa-Pro peptide bond conformation on the basis of backbone chemical shifts and the amino acid sequence. Using a chemical shift database of proteins of known structure together with the PDB-extracted amino acid preference of cis Xaa-Pro peptide bonds, a cis/trans probability score is calculated from the backbone and (13)C(beta) chemical shifts of the proline and its neighboring residues. For an arbitrary number of input chemical shifts, which may include Pro-(13)C(gamma), Promega calculates the statistical probability that a Xaa-Pro peptide bond is cis. Besides its potential as a validation tool, Promega is particularly useful for studies of larger proteins where Pro-(13)C(gamma) assignments can be challenging, and for on-going efforts to determine protein structures exclusively on the basis of backbone and (13)C(beta) chemical shifts.

SUBMITTER: Shen Y

PROVIDER: S-EPMC2847849 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Prediction of Xaa-Pro peptide bond conformation from sequence and chemical shifts.

Shen Yang Y Bax Ad A

Journal of biomolecular NMR 20091230 3

We present a program, named Promega, to predict the Xaa-Pro peptide bond conformation on the basis of backbone chemical shifts and the amino acid sequence. Using a chemical shift database of proteins of known structure together with the PDB-extracted amino acid preference of cis Xaa-Pro peptide bonds, a cis/trans probability score is calculated from the backbone and (13)C(beta) chemical shifts of the proline and its neighboring residues. For an arbitrary number of input chemical shifts, which ma ...[more]

PMID: 20041279

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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

Prediction of Xaa-Pro peptide bond conformation from sequence and chemical shifts.

Publications

Prediction of Xaa-Pro peptide bond conformation from sequence and chemical shifts.

Similar Datasets

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