Calculation of pKa values of carboxylic acids: Application to bilirubin

One of the major factors in the interactions of proteins with other molecules is the dissociation constant for a weakly acidic or basic group, generally expressed as the pKa. We have critically evaluated various quantum mechanical (QM) methods for calculation of protonation states of carboxylic acids including bilirubin. We calculated pKa values of various carboxylic acids by using quantum-chemical calculations in conjunction with Langevin dipoles and solvent reaction field method of Tomasi and co-workers. We studied formic acid, acetic acid, nicotinic acid and bilirubin. We demonstrated that the calculated pKa values compare well with the experiment if flexible basis sets of at least 6-31+G(d,p) size and Langevin dipoles solvation model are used. Results are discussed in terms of bilirubin transport by bilitranslocase.