A fast and accurate method for predicting pKa of residues in proteins

Predicting the pH-activities of residues in proteins is an important problem in enzyme engineering and protein design. A novel predictor called 'Pred-pK(a)' was developed based on the physicochemical properties of amino acids and protein 3D structure. The Pred-pK(a) approach considers the influence of all other residues of the protein to predict the pK(a) value of an ionizable residue. An empirical equation was formulated, in which the pK(a) value was a distance-dependent function of physicochemical parameters of 20 amino acid types, describing their electrostatic and van der Waals interaction, as well as the effects of hydrogen bonds and solvation. Two sets of coefficients, {a(alpha)} and {b(l)}, were used in the predictor: {a(alpha)} is the weight factors of 20 amino acid types and {b(l)} is the weight factors of physicochemical properties of amino acids. An iterative double least square procedure was proposed to solve the two sets of weight factors alternately and iteratively in a training set. The two coefficient sets {a(alpha)} and {b(l)} thus obtained were used to predict the pK(a) values of residues in a protein. The average predictive error is +/-0.6 pH in less than a minute in common personal computer.