Inclusion of ionization states of ligands in affinity calculations

Donnini, Serena, Villa, Alessandra, Groenhof, Gerrit, Mark, Alan E., Wierenga, Rik K. and Juffer, Andre H. (2009) Inclusion of ionization states of ligands in affinity calculations. Proteins: Structure, Function and Bioinformatics, 76 1: 138-150. doi:10.1002/prot.22326


Author Donnini, Serena
Villa, Alessandra
Groenhof, Gerrit
Mark, Alan E.
Wierenga, Rik K.
Juffer, Andre H.
Title Inclusion of ionization states of ligands in affinity calculations
Journal name Proteins: Structure, Function and Bioinformatics   Check publisher's open access policy
ISSN 0887-3585
Publication date 2009-07-01
Year available 2008
Sub-type Article (original research)
DOI 10.1002/prot.22326
Open Access Status
Volume 76
Issue 1
Start page 138
End page 150
Total pages 13
Place of publication United States
Publisher Wiley Interscience
Language eng
Subject C1
Abstract When estimating binding affinities of a ligand, which can exists in multiple forms, for a target molecule, one must consider all possible competing equilibria. Here, a method is presented that estimates the contribution of the protonation equilibria of a ligand in solution to the measured or calculated binding affinity. The method yields a correction to binding constants that are based on the total concentration of inhibitor (the sum of all ionized forms of the inhibitor in solution) to account for the complexed form of the inhibitor only. The method is applied to the calculation of the difference in binding affinity of two inhibitors, 2-phosphoglycolate (PGA) and its phoshonate analog 3-phosphonopropionate (3PP), for the glycolytic enzyme triosephosphate isomerase. Both inhibitors have three titrating sites and exist in solution as a mixture of different forms. In this case the form that actually binds to the enzyme is present at relative low concentrations. The contributions of the alternative forms to the difference in binding energies is estimated by means of molecular dynamics simulations and corrections. The inhibitors undergo a pKa shift upon binding that is estimated by ab initio calculations. An interesting finding is that the affinity difference of the two inhibitors is not due to different interactions in the active site of the enzyme, but rather due to the difference in the solvation properties of the inhibitors. Protein 2009. © 2008 Wiley-Liss, Inc.
Keyword binding free energy
effective affinity
molecular dynamics
pK calculations
protonation equilibria
thermodynamic integration
trioephosphate isomerase
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Published Online: 18 Nov 2008

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
 
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Created: Thu, 03 Sep 2009, 18:03:58 EST by Mr Andrew Martlew on behalf of School of Chemistry & Molecular Biosciences