Conformational Analysis of Furanoid ε-Sugar Amino Acid Containing Cyclic Peptides by NMR Spectroscopy, Molecular Dynamics Simulation, and X-ray Crystallography: Evidence for a Novel Turn Structure

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 ε-SAA III
and several amino acids were elucidated to study the preferred conformation of such an ε-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 αIIbβ3-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 ε-SAA III is able to introduce an unusual intraresidue
hydrogen bond-stabilized β-turn-like conformation in two of the three cyclic structures.