Factors affecting conformations of cyclic polypeptides in the crystalline state

Abstract

Criteria for geometrical parameters, such as bond lengths, bond angles and torsional angles, are needed for building models of polypeptides based on spectral data and/or minimum energy calculations. Some assumptions that are made frequently are: that the most stable form of the peptide unit is planar and in the trans conformation; that the maximum number of hydrogen bonds will be formed: that peptides dissolved in nonpolar solvents will turn their polar groups toward the interior of the molecule (and form intramolecular hydrogen bonds), whereas those dissolved in polar solvents will turn their polar groups toward the exterior. The validity of such assumptions has been examined by crystal structure analyses of a variety of cyclic peptides crystallized under varying conditions. The cyclic backbone in telrapeptides, both natural and synthetic, has been found to assume four different conformations, cis trans cis trans with a center of inversion or with a twofold rotation axis, and trans trans trans trans with a center of inversion or with a twofold rotation axis. A pair of similar cyclic pentapeptides have been found to be rotational isomers, where the backbone conformation (all trans) remains the same, but the side chains progress by one peptide unit around the ring. A hexapeptide analogue crystallized from (CH3)2SO/(CH3)2CO and from H2O/(CH3)2CO crystallizes in different space groups. Four molecules of the hexapeptide aggregate by intermolecular hydrogen bonding to form an almost identical large cavity in each case; however, in one crystal the cavity is filled with water molecules, which make extensive hydrogen bonds to the polar groups of the surrounding peptide molecules, whereas in the other case, the cavity contains (CH3)2SO that participates in only one hydrogen bond to the peptide and otherwise presents a lipophilic surface toward the polar lining of the cavity. A similar phenomenon has been observed in the large-diameter channels formed by antamanide molecules (cyclic decapeptide) where the channel is occupied either by many water molecules in definite sites and hydrogen bound to the peptide molecules, or by nonpolar disordered n-hexane molecules. In the latter two examples the character of the solvent does not influence the conformation of the peptide.