DOI: 10.1002/prot.22102. Very fast prediction and rationalization of p<i>K</i><sub>a</sub> values for protein

Very fast prediction and rationalization of pKa values for protein–ligand complexes

10.1002/prot.22102

Crossref journal-article

Wiley

Proteins: Structure, Function, and Bioinformatics (311)

Abstract

AbstractThe PROPKA method for the prediction of the pKa values of ionizable residues in proteins is extended to include the effect of non‐proteinaceous ligands on protein pKa values as well as predict the change in pKa values of ionizable groups on the ligand itself. This new version of PROPKA (PROPKA 2.0) is, as much as possible, developed by adapting the empirical rules underlying PROPKA 1.0 to ligand functional groups. Thus, the speed of PROPKA is retained, so that the pKa values of all ionizable groups are computed in a matter of seconds for most proteins. This adaptation is validated by comparing PROPKA 2.0 predictions to experimental data for 26 protein–ligand complexes including trypsin, thrombin, three pepsins, HIV‐1 protease, chymotrypsin, xylanase, hydroxynitrile lyase, and dihydrofolate reductase. For trypsin and thrombin, large protonation state changes (|n| > 0.5) have been observed experimentally for 4 out of 14 ligand complexes. PROPKA 2.0 and Klebe's PEOE approach (Czodrowski P et al. J Mol Biol 2007;367:1347–1356) both identify three of the four large protonation state changes. The protonation state changes due to plasmepsin II, cathepsin D and endothiapepsin binding to pepstatin are predicted to within 0.4 proton units at pH 6.5 and 7.0, respectively. The PROPKA 2.0 results indicate that structural changes due to ligand binding contribute significantly to the proton uptake/release, as do residues far away from the binding site, primarily due to the change in the local environment of a particular residue and hence the change in the local hydrogen bonding network. Overall the results suggest that PROPKA 2.0 provides a good description of the protein–ligand interactions that have an important effect on the pKa values of titratable groups, thereby permitting fast and accurate determination of the protonation states of key residues and ligand functional groups within the binding or active site of a protein. Proteins 2008. © 2008 Wiley‐Liss, Inc.

Bibliography

Bas, D. C., Rogers, D. M., & Jensen, J. H. (2008). Very fast prediction and rationalization of pKa values for proteinâligand complexes. Proteins: Structure, Function, and Bioinformatics, 73(3), 765â783. Portico.

Authors 3

Delphine C. Bas (first)
David M. Rogers (additional)
Jan H. Jensen (additional)

References 78 Referenced 991

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Dates

Type	When
Created	17 years, 2 months ago (May 22, 2008, 12:48 p.m.)
Deposited	1 year, 10 months ago (Oct. 15, 2023, 11:31 a.m.)
Indexed	1 hour, 9 minutes ago (Aug. 21, 2025, 9:37 a.m.)
Issued	17 years, 2 months ago (May 22, 2008)
Published	17 years, 2 months ago (May 22, 2008)
Published Online	17 years, 2 months ago (May 22, 2008)
Published Print	16 years, 9 months ago (Nov. 15, 2008)

Funders 0

None

BibTeX

@article{Bas_2008, title={Very fast prediction and rationalization of pKa values for protein–ligand complexes}, volume={73}, ISSN={1097-0134}, url={http://dx.doi.org/10.1002/prot.22102}, DOI={10.1002/prot.22102}, number={3}, journal={Proteins: Structure, Function, and Bioinformatics}, publisher={Wiley}, author={Bas, Delphine C. and Rogers, David M. and Jensen, Jan H.}, year={2008}, month=may, pages={765–783} }

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