Antigelling and antisickling bisphenyl oligopeptides and peptide analogues have similar structural features

Abstract

Single-crystal X-ray diffraction was used to determine the three-dimensional structures of two antigelling oligopeptides, L-lysyl-L-phenylalanyl-L-phenylalanine and L-phenylalanylglycylglycyl-D-phenylalanine, and two antisickling peptide analogues, L-phenylalanine benzyl ester and N-phenylacetyl-L-phenylalanine. Although these bisphenyl compounds are chemically quite different from one another, they demonstrate unusual structural similarities: The molecules have compact conformations in which the two phenyl rings are positioned approximately 5 A apart with interplanar angles approaching 90 degrees, thereby making intramolecular edge-to-face interactions. In addition, the polar atoms, nitrogen and oxygen, are in close proximity without forming intramolecular hydrogen bonds. The relative spatial distribution of polar and nonpolar atoms renders the structures compact and amphipathic. The intramolecular edge-to-face interaction between two aromatic rings, which brings a hydrogen atom with relative positive charge near the pi-electron cloud with relative negative charge, is enthalpically favorable and maintains the molecules in a compact and amphipathic conformation. Nonbonded potential energy calculations were used to characterize the energetics of the aromatic-aromatic interaction, and they showed that the observed geometry is stabilized enthalpically by a favorable interaction on the order of -1 to -2 kcal/mol. Structural differences between the two antisickling and the two antigelling agents suggest that molecular volume limits red cell membrane passage. These data provide a molecular structural framework from which to design and synthesize amphipathic bisphenyl compounds that both bind to deoxy sickle cell hemoglobin and cross the erythrocyte membrane.

New chemical and stereochemical applications of organoiron complexes

“…The mutual interaction of aromatic rings of aromatic amino acid residues in proteins and peptides has been discussed [ 1274 ]. Incorporation into peptides and proteins of amino acids having a covalent link between their aromatic rings would give the stabilization of the tertiary structure of a protein, with interesting biological consequences.…”

The structure of an antisickling agent, N-phenylacetyl-L-phenylalanine monohydrate

“…These structures are stabilized by a weakly polar interaction, which results from the characteristic segregation of partial charges in aromatic moieties (Burley & Petsko, 1986). A mechanism of antisickling action has been proposed by Burley, ,Wang, Votano & Rich (1987).…”

The structure of an antisickling agent, L-phenylalanine benzyl ester monochloride

“…Burley & Wang (1987a,b) and Fujii, Burley & Wang (1987). A mechanism of antisickling action was proposed by Burley, Wang, Votano & Rich (1986). The intra-and intermolecular edge-to-face interactions between phenyl rings are enthalpically favorable (Burley& Petsko, 1986).…”