Tautomeric equilibria of pyridoxal-5'-phosphate (vitamin B6) and 3-hydroxypyridine derivatives: a theoretical study of solvation effects.

The tautomeric equilibria of a series of 3-hydroxypyridine derivatives including pyridoxal-5'-phosphate (PLP), the active form of vitamin B(6), have been studied using density functional calculations (B3LYP/6-311+G//B3LYP/6-31G) in the gas phase and in different solvents. Three different approaches, namely continuum, discrete, and hybrid (combined discrete/SCRF), were employed to investigate the effects of solvation on the tautomeric equilibria. In all cases, the neutral hydroxy form is significantly more stable than the zwitterionic oxo form (by 43-56 kJ mol(-)(1)) in the gas phase. The tautomeric energies reduce substantially in the presence of a polarizable dielectric medium. However, the neutral form is calculated to be the dominant form in nonpolar and aprotic polar solvents. On the other hand, a reversal of tautomeric equilibrium, in favor of the zwitterionic form, is predicted in an aqueous medium. This study highlights the role of both water molecules and bulk solvent effect in influencing the tautomeric equilibria of the PLP related compounds. A combination of explicit microsolvation and continuum reaction field is required to account fully for the energetic effect of aqueous solvation. The tautomeric free energy differences (deltaG(298)) of PLP in the gas phase and in aprotic polar (epsilon = 40) and aqueous media are predicted to be 47, 22, and -29 kJ mol(-)(1), respectively.