Prediction and rationalization of protein pK a values using QM and QM/MM methods

Jan H. Jensen, Hui Li, Andrew D. Robertson, Pablo A. Molina

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


We describe the development and application of a computational method for the prediction and rationalization of pK a values of ionizable residues in proteins, based on ab initio quantum mechanics (QM) and the effective fragment potential (EFPs) method (a hybrid QM/MM method). The theoretical developments include (1) a covalent boundary method based on frozen localized orbitals, (2) divide-and-conquer methods for the ab initio computation of protein EFPs consisting of multipoles up to octupoles and dipole polarizability tensors, (3) a method for computing vibrational free energies for a localized molecular region, and (4) solutions of the polarized continuum model of bulk solvation equations for protein-sized systems. The QM-based pK a prediction method is one of the most accurate methods currently available and can be used in cases where other pK a prediction methods fail. Preliminary analysis of the computed results indicate that many pK a values (1) are primarily determined by hydrogen bonds rather than long-range charge-charge interactions and (2) are relatively insensitive to large-scale dynamical fluctuations of the protein structure.

Original languageEnglish (US)
Pages (from-to)6634-6643
Number of pages10
JournalJournal of Physical Chemistry A
Issue number30
StatePublished - Aug 4 2005
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

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