Application to the Determination of Solute Structural Properties

6.6.1 The Case of Zwitterionic Amino Acids

The lipophilic expression of the side-chains of amino acids is of interest from biochemical and physicochemical viewpoints. On the one hand, the folding and stability of proteins are highly related to the hydrophobic nature of amino acid residues [29]. On the other hand, intra- and intermolecular interactions of zwitterionic amino acids in solu tion are reflected in their solvation/hydration behavior [30] and hence lipophilicity. Since the literature log Pocl values for these highly hydrophilic compounds were obtained from the SF method and, in some cases, varied markedly, the CPC method appeared to us an appropriate technique to reveal the structure-lipophilicity relationships of zwitterionic amino acids.

To see the lipophilic expression of the methylene groups in the side-chains of flexible a-amino acids, the log D] values (distribution coefficient measured at isoelectric point) of a-amino acids with an alkyl chain length of 0 (glycine) to 4 (norleucine) were determined [31], Figure 8 shows the non-additive log Dl increments of methylene groups.

log D1

Norleucine

Norvaline

a-Amiiiobutyric acid

Alanine

Glycine

Figure 8. Nonadditive log D' increments of methylene groups in the flexible side-chains of zwitterionic amino acids. The lipophilic expression of methylene groups near the zwitterionic dipole is partially masked. Only when the fourth methylene group is added, does it gain a normal log D] increment of a methylene group (ca. 0.6).

Indeed, abnormal lipophilic increments of methylene groups are usually observed when they are in close proximity to polar moieties due, at least in part, to the electronic structure of methylene groups near polar entities differing from that of distal ones. However, hydration features must also be considered here since proximity effects have been postulated to be a consequence of hydration effects.

The influence of intercharge distance on lipophilicity was also examined using con-formationally defined positional isomers of piperidinyl carboxylic acids, i. e., pipecolic acid, nipecotic acid, and isonipecotic acid [31]. A plot of log D1 against the intercharge distance reveals that increasing the intercharge distance decreases the log D1 values with a slope of c. 0.4 units A-1.

0 0

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