Conformational analysis of potent sweet taste ligands by NMR and computer simulations

Abstract

We report the conformational analysis by 1H-nmr and computer simulations of five potent sweet molecules, N-(3,3-dimethylbutyl)-L-aspartyl-S-(α-methyl)phenylalanine methylester (1; 5000 times more potent than sucrose), L-aspartyl-D-valine (S)-α-methoxycarbonylmethylbenzylamide (2; 1400 times more potent than sucrose), L-aspartyl-D-valine α-phenylcyclopentylamide (3; 1200 times more potent than sucrose), L-aspartyl-D-α-aminobutyric acid (S)-α-cyclohexylpropylamide (4; 2300 times more potent than sucrose), and L-aspartyl-D-valine (R)-α-methylthiomethylbenzylamide (5; 3000 times more potent than sucrose). The “L-shaped” structure, which we believe to be responsible for sweet taste, is accessible to all five sweet compounds in solution. This structure is characterized by a zwitterionic ring formed by the A-H and B containing moieties located in the +y axis and by the hydrophobic group X pointing into the +x axis. Other accessible conformations of these flexible molecules are extended conformations with the A-H and B containing moieties in the +y axis and the hydrophobic group X pointing in the −y axis and reversed L-shaped structures with the hydrophobic group X projecting along the −x axis. The remarkable potency of the N-alkylated compound 1 supports our recent hypothesis that a second hydrophobic binding domain in addition to interactions arising from the L-shaped structure leads to an enhancement of sweetness potency. © 1999 John Wiley & Sons, Inc. Biopoly 49: 525–539, 1999