Cysteine and aspartic acids are common amino acid building blocks for peptides and proteins. In connection with our studies for acid-base properties of cysteine-containing peptide, pKa measurements of a group of amino acids and several of their analogs were carried out by using <sup>1</sup>H NMR spectroscopy along with pH titration. For titration, an acidic aqueous solution of a compound was titrated with NaOH solution, from its acid form to its basic form. The change of chemical shift associated with the -CH<sub>2</sub>- group of the amino acid (or analog) was monitored. We observed that, for certain compounds, the two methylene hydrogens presented very differently at one pH titration end, compared to the other titration end. At one titration end, the methylene hydrogens presented either as identical or with only a small difference in chemical shift value (&lt;0.05 Δppm); but they presented, at the other pH end, with a large chemical shift value difference (0.4–0.5 Δppm) and associated characteristic coupling patterns. We found this pattern in cysteine, cysteine analogs, methylthioacetic acid sulfoxide, aspartic acid and an aspartic acid analog. We attribute this observation to a six-member ring formation via an intramolecular salt-bridge involving a sodium ion or hydrogen-bonding between the carboxyl group and a heteroatom (oxygen or nitrogen), forcing the two methylene hydrogens into axial and equatorial positions in the ring structure. Those observed patterns are consistent with the anisotropic effect and the Karplus equation for an axial/equatorial hydrogen of a six-member ring structure. Additionally, we carried out computational studies using density functional theory with an explicit solvent model. The molecular modeling supports the stability of these proposed ring structures.

Ring structure formation of amino acids and analogs via sodium adduct and hydrogen bonding

ACS Spring Meeting 2021

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