title: Conformational analysis of furanoid epsilon-sugar amino acid containing cyclic peptides by NMR spectroscopy, molecular dynamics simulation, and X-ray crystallography: evidence for a novel turn structure.
abstract: Sugar amino acids (SAAs) are useful building blocks for the design of peptidomimetics and peptide scaffolds. The three-dimensional structures of cyclic hybrid molecules containing the furanoid epsilon-SAA III and several amino acids were elucidated to study the preferred conformation of such an epsilon-SAA and its conformational influence on the backbone of cyclic peptides. NMR-based molecular dynamics simulations and empirical calculations of the cyclic tetramer 1, consisting of two copies of the SAA residue and two amino acids, revealed that it is conformationally restrained. The two SAA residues adopt different conformations. One of them forms an unusual turn, stabilized by an intraresidue nine-member hydrogen bond. The methylene functionalities of the other SAA residue are positioned in such a way that an intraresidue H bond is not possible. The X-ray crystal structure of 1 strongly resembles the solution conformation. Molecular dynamics calculations in combination with NMR analysis were also performed for compounds 2 and 3, which contain the RGD (Arg-Gly-Asp) consensus sequence and were previously shown to inhibit alpha(IIb)beta(3)-receptor-mediated platelet aggregation. The biologically most active compound 2 adopts a preferred conformation with the single SAA residue folded into the nine-member H bond-containing turn. Compound 3, containing an additional valine residue, as compared with compound 2, is conformational flexible. Our studies demonstrate that the furanoid epsilon-SAA III is able to introduce an unusual intraresidue hydrogen bond-stabilized beta-turn-like conformation in two of the three cyclic structures.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Renate M
authors.initials: RM
authors.lastname: van Well
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Cornelis
authors.initials: C
authors.lastname: Altona
authors.forename: Kees
authors.initials: K
authors.lastname: Erkelens
authors.forename: Gregg
authors.initials: G
authors.lastname: Siegal
authors.forename: Mark
authors.initials: M
authors.lastname: van Raaij
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Llamas-Saiz
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Jacques H
authors.initials: JH
authors.lastname: van Boom
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000606:Amino Sugars / Q000737:chemistry; D002236:Carbohydrate Conformation; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005663:Furans / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013400:Sugar Acids / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D000606:Amino Sugars; D005663:Furans; D010456:Peptides, Cyclic; D013400:Sugar Acids