Computation of protein pK's by an integrated DFT/PCM approach

This paper describes the extension of our computational strategy for pK predictions of small mols. to large solutes. The basic computational tool results from the coupling of quantum mech. methods rooted in the d. functional theory with the most recent version of the Polarizable Continuum Model. However, a third level is introduced, which includes solute regions far from the reactive center, which are described at a simplified level. This partition, together with the recent implementation of fast cavity generation, powerful iterative solvers, and fast multipole technol., allows us to tackle solutes of the dimension of a small protein. The problems and perspectives of this methodol. are analyzed with special ref. to the behavior of different Polarizable Continuum Model versions on the challenging playground represented by the pK's of the different histidine residues occurring in the human prion protein.