title: Computation of pH-dependent binding free energies.
abstract: Protein-ligand binding accompanies changes in the surrounding electrostatic environments of the two binding partners and may lead to changes in protonation upon binding. In cases where the complex formation results in a net transfer of protons, the binding process is pH-dependent. However, conventional free energy computations or molecular docking protocols typically employ fixed protonation states for the titratable groups in both binding partners set a priori, which are identical for the free and bound states. In this review, we draw attention to these important yet largely ignored binding-induced protonation changes in protein-ligand association by outlining physical origins and prevalence of the protonation changes upon binding. Following a summary of various theoretical methods for pKa prediction, we discuss the theoretical framework to examine the pH dependence of protein-ligand binding processes.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093.
authors.forename: M Olivia
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093.|Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093.|National Biomedical Computation Resource, University of California San Diego, La Jolla, CA, 92093.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011506:Proteins
keywords: binding free energy; pH dependence; pKa; protein-ligand binding; protonation