Prediction of pKa values for amino acids and peptides

by Zhang, Shuming; Baker, Jon; Pulay, Peter

Previously [232nd ACS meeting], we have developed a protocol for the prediction of org. pKa values in aq. solns. Geometries of both forms are optimized at the OLYP/3-21G(d)-COSMO level, relative energies, ΔH, are detd. at the OLYP/6-311+G(d,p)-COSMO level, and acidities are calcd. as pKa=AΔH+B where A and B are empirical consts., detd. from fitting known pKa values. Seven different A,B pairs are used for various functional groups. The mean abs. deviation (MAD) for carboxylic acids was below 0.2 pKa unit. Our protocol predicts the carboxyl pKa in α amino acids and small peptides reasonably (MAD<0.5) but greatly overestimates the pKa of the amino group in free amino acids (by about 2 pKa units). Using sep. parameters for the amino group, we are able to predict the amino pKa in α amino acids with a MAD of 0.44 pKa unit, and in di- and tripeptides with a MAD of 0.64.