Progress in the prediction of pK_avalues in proteins

Abstract

The pKa-cooperative aims to provide a forum for experimental and theoretical researchers interested in protein pKa values and protein electrostatics in general. The first round of the pKa-cooperative, which challenged computational labs to carry out blind predictions against pKas experimentally determined in the laboratory of Bertrand Garcia-Moreno, was completed and results discussed at the Telluride meeting (July 6–10, 2009). This paper serves as an introduction to the reports submitted by the blind prediction participants that will be published in a special issue of PROTEINS: Structure, Function and Bioinformatics. Here we briefly outline existing approaches for pKa calculations, emphasizing methods that were used by the participants in calculating the blind pKa values in the first round of the cooperative. We then point out some of the difficulties encountered by the participating groups in making their blind predictions, and finally try to provide some insights for future developments aimed at improving the accuracy of pKa calculations.

Chaperone activation by unfolding

“…With its small size (active conformation <10 kDa), its independence from any cochaperones or ATP, and our demonstration that it is active as a monomer, HdeA is an example of the minimal protein unit necessary for chaperone function. The fact that HdeA's activity is regulated by pH makes it particularly attractive, because recent developments have made it possible to predict the effects of pH on protein structure accurately on a residue-by-residue basis (54,55). Such calculations, coupled with site-specific mutagenesis, have allowed us to design and isolate constitutively active mutants of HdeA.…”

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

“…Computational methods using molecular dynamics (MD) simulations an/or Monte Carlo (MC) sampling have been developed with considerable success for predicting protein pK a values (see reviews [28][29][30] ). Often referred to as constant pH MD (CPHMD) simulations, the titration coordinate is typically implemented in either a discrete manner [31][32][33][34][35][36][37][38][39][40][41][42][43] where protonation states are modified with an MC step at some regular MD interval or using a continuous function [44][45][46] that describes the protonation state via the k dynamics method developed by Brooks and coworkers.…”

Some Critical Aspects of Molecular Interactions Between Drugs and Receptors

“…Note that at this stage, the interactions are supposed to be quite weak and not to affect the energetics of individual molecules, including the pK a 's of ionizable groups. Thus, if the structures of unbound monomers are available, one could apply standard pK a calculations [117,118] and be able to estimate the protonation states at the desired pH. Unfortunately, it is quite likely that there will be no a priori information about the physiological pH at which the complex forms, but it is necessary to predict it by either using the information about sub-cellular location provided in the Protein Data bank (PDB) [119] or by carrying out additional investigations to search the literature for homologous annotated protein(s).…”

“…In terms of predicting protonation states of proteins and receptor-ligand complexes, one can utilize standard pKa calculations if the structures of both the unbound and bound entities are available [117,151]. The problem becomes more complicated if several groups change protonation state [71].…”