THERMODYNAMIC DESCRIPTION OF A CONTACT AND SOLVENT-SEPARATED ION-PAIR AS A FUNCTION OF SOLVATION - A MODEL FOR SALT BRIDGES AND PROTON-TRANSFER REACTIONS IN BIOLOGY

Solvation free energies for 1alpha-amino-8abeta-methylbicyclo[4.4.0]decane-7alpha-carboxylic acid (1), a cis-decalin amino acid that populates two conformers in which either an intramolecular contact or solvent-separated ion pair is formed, have been determined in a wide range of solvents (CDCl3 to D2O). The nature of the ion pairs, and the range of conditions evaluated, mimicked ion pairs found in biomolecules (''salt bridges''). Conformational and proton-transfer equilibria were evaluated from changes in H-1 NMR coupling constants and chemical shifts, respectively, and the ion pair DELTAGs could be extracted directly. Correlations of ion pair DELTAGs with solvent polarity scales (E(T)(30) values) and solvent hydrogen bond acidities demonstrated the importance of stabilizing the carboxylate ion in low-polarity solvents. Comparisons of ion pair stability for contact and separated ion pairs revealed that the electrostatic attraction is secondary to relative solvent dielectric and hydrogen bond acidity at stabilizing the interaction; conversely, solvent hydrogen bond basicity did not contribute to the stabilization. The failure of bulk solvent properties, such as the Kirkwood-Onsager dielectric epsilon(K), to adequately correlate ion pair energetics (and previously, hydrogen bond energetics: Beeson, C.; Pham, N.; Shipps, G.; Dix, T. A. J. Am. Chem. Soc. 1993, 115, 6803) indicated the limited applicability of macroscopic electrostatic models; rather, the correlations between electrostatic DELTAGs and empirical solvent parameters amplified the need for molecular solvation models. Ultimately, the sensitivity of electrostatics to solvent donor-acceptor properties argues that a successful treatment of protein structure must be done on the molecular level, by evaluating local interactions and solvation. The results thus have significance for a description of electrostatic interactions in biological structure and function.