Ab Initio Simulation of pH-Sensitive Biomarkers in Magnetic Resonance Imaging

An ab initio simulation scheme is introduced as a theoretical prescreening approach to facilitate and enhance the research for pH-sensitive biomarkers. The proton ¹H and carbon ¹³C nuclear magnetic resonance (NMR) chemical shifts of the recently published marker for extracellular pH, [1,5-¹³C₂]zymonic acid (ZA), and the as yet unpublished (Z)-4-methyl-2-oxopent-3-enedioic acid (OMPD) were calculated with ab initio methods as a function of the pH. The influence of the aqueous solvent was taken into account either by an implicit solvent model or by explicit water molecules, where the latter improved the accuracy of the calculated chemical shifts considerably. The theoretically predicted chemical shifts allowed for a reliable NMR peak assignment. The pK_a value of the first deprotonation of ZA and OMPD was simulated successfully whereas the parametrization of the implicit solvent model does not allow for an accurate description of the second pK_a. The theoretical models reproduce the pH-induced chemical shift changes and the first pK_a with sufficient accuracy to establish the ab initio prescreening approach as a valuable support to guide the experimental search for pH-sensitive biomarkers.