Conformation-activity relationship of sweet molecules. Comparison of aspartame and naphthimidazolesulfonic acids

Abstract

The shape of the active site of the receptor for sweet molecules was previously defined on the basis of a combination of both rigid (saccharins) and flexible (aspartame) molds. In this paper, the sweetness receptor is refined with use of the shapes of 3-anilino-2-styryl-3H-naphtho[1,2-d]imidazolesulfonate (sweet) and of 3-anilino-2-phenyl-3H-naphtho[1,2-d]imidazolesulfonate (tasteless), two large and almost completely rigid tastants. The minimum-energy conformations of the flexible portions of these tastants have been determined by using a detailed conformational analysis based on ab initio calculations. The refined receptor site is still consistent with all previously examined sweet molecules. In order to unequivocally assign the prochiral beta-CH2 protons of the Phe moiety of aspartame, (2S,3S)-[2H]-alpha-L-Asp-L-PheOMe was synthesized and examined by 500-MHz 1H NMR spectroscopy. The results indicate that the minimum-energy conformation for aspartame in water, DMSO-d6, and CDCl3 (as a crown ether complex) is different from that originally proposed (FIIDII instead of FIDII, according to a notation referred to the side chains). Although this conformation is not directly consistent with the shape of the sweet receptor, the interconversion of FIIDII to FIDII was found to require only 1 kcal/mol. Furthermore, a 120-ps molecular dynamics simulation in vacuo confirms the high flexibility of aspartame and the accessibility of the FIDII conformer whose topology is fully consistent with our model.

Evolution of the Sweetness Receptor in Primates. I. Why Does Alitame Taste Sweet in all Prosimians and Simians, and Aspartame only in Old World Simians?

“…(Feinstein et al, 1991), (b) and (<:)• the two preferred and quasi-isoenergetic conformations of aspartame in solution (Castiglione-Morelli etal., 1990). Contrary to the preceding assertions, since the present work substantiates the existence of two distinct hydrophobic recognition sites within the sweetness receptor of humans, apes and Old World monkeys, it follows that alitame must interact with the sweetness receptor in an L-shaped conformation (Figure 7a) according to the Goodman model Feinstein et aL, 1991) and aspartame must interact with the sweetness receptor in its extended conformation (Figure 7b) in agreement with the Temussi proposal (Lelj et aL, 1976;Temussi et aL, 1978Temussi et aL, , 1991Castiglione-Morelli et aL, 1990).…”

“…According to Feinstein et al (1991), the preferred conformation of alitame can be described as possessing an L shape, with the COO~ and NH 3 + containing aspartyl moiety as the stem of the L and the hydrophobic tetramethylthietanyl moiety as the base of the L, nearly perpendicular to the aspartyl residue backbone (Figure 7a). For aspartame, the current opinion is that aspartame in solution can exist under two quasi-isoenergetic conformations in dynamic equilibrium (Castiglione-Morelli et al, 1990;Taylor et al, 1991), one in an extended conformation with the phenyl ring approximately parallel to the zwitterionic ring of the aspartyl residue and in an almost direct line widi the aspartyl residue axis (Figure 7b), the other in an L-shaped conformation rather similar to the overall conformation of alitame, with the phenyl group roughly perpendicular to the aspartyl residue (Figure 7c). The interconversion of the reshaped conformation (which appears to be the most populated conformation in solution) to the extended conformation requires less than 1 kcal/mol, a modest value that can be easily compensated for by the interaction with receptor (Castiglione-Morelli et al, 1990).…”

Identification and characterisation of the E951 artificial food sweetener by vibrational spectroscopy and theoretical modelling

“…The C6-C5-C13-O19 angle of the E951 molecule is in the gauche-range (averaged value −75.7 • ), locating the carboxyl C13 atom in close proximity to the amino N atoms. [26] The dihedral angles of the E951 molecule in the four crystal forms are almost the same values, [2,9 -12] suggesting that the E951 molecule adopts almost identical conformation. Relatively long C-C bond distances of the phenyl ring are also common for all crystal forms.…”

“…The C-C bond lengths of the phenyl ring have values situated between 139.0 pm and 141.1 pm, which are considerably large for the C-C distance in the phenyl ring, a known particularity of the phenyl structures. [10,26] In the alkanedicarboxylic acids with even number of carbon atoms, the distribution of the C-C bond lengths along the aliphatic carbon chain is alternative, long and short bond lengths, while for the alkanedicarboxylic acids with odd number of carbon atoms the distribution is normal. [31,32] This finding is in good agreement with the theoretical calculations performed, where the C-C bond lengths of the aliphatic carbon chain are in the range of 150.8 pm to 156.6 pm (Table S1) (Supporting Information).…”

“…[26,27] The N-C-R torsional angles of the E951 molecule with values situated between 106.7 • and 124.4 • (Table S1, Supporting Information) may explain the differentiation between its conformation in the solid state and in solution. The intramolecular cyclisation of the E951 molecule in solution is possible for the low-energy conformers and at high temperatures, which suggest that E951 molecule is very flexible.…”