A Comprehensive Computational Study on the Thermodynamics and Kinetics of Tetrahydrobiopterin Regeneration Process

Abstract

Tetrahydrobiopterin, one of the most crucial enzymatic cofactors acquired through biological synthesis and self‐regeneration in the human body. During this process, it undergoes oxidation and deprotonation, forming quinonoid‐dihydrobiopterin, which then tautomerizes to yield dihydrobiopterin. This study presents the thermodynamic and kinetic properties of each stage using theoretical calculations. Redox potentials and pKa values are determined using the Born‐Haber cycle in implicit solvent models. Redox metabolites are characterized from calculated absorption spectra using time‐dependent density functional theory. Rate constants for tautomerization steps are computed using Eyring's Transition State Theory, incorporating Wigner's tunneling correction. The N3 atom is identified as the most probable deprotonation site for H3B+. Spectral properties of intermediates are elucidated, highlighting key electronic transitions. Tautomerization steps occur through vibrational bending modes, and tunneling corrections significantly increase reaction rates. These findings provide a comprehensive understanding of the thermodynamics and kinetics of tetrahydrobiopterin regeneration, aiding in the modulation of its biological activity.