MODELING OF PROTEIN CONFORMATIONAL FLUCTUATIONS IN PK(A) PREDICTIONS

A method is presented to account for conformational fluctuations of a protein in predicting the pK(a) values of its titrating groups. Confor mations of the protein are generated by conventional molecular dynamic s or Monte Carlo simulations, in which the protonations of the titrati ng groups are fixed. For each protein conformation, the electrostatic free energies required to add a proton charge to a titrating group whi le other groups are either unprotonated or protonated are calculated w ithin a dielectric continuum model. These are used to determine the me an protonations of the titrating groups in the conformation at a serie s of pH values. The mean protonations are then used to determine the r elative weight of the particular conformation with the titrating group s having all possible protonations. A conformationally averaged mean p rotonation for each titrating group is finally obtained by the weighte d sum of the group's mean protonations in all the conformations. This method is applied to yeast iso-1-ferricytochrome c. The predicted pK(a ) values are in general agreement with experimental results. (C) 1997 Academic Press Limited.