Quantitative assessment of protein interaction with methyl-lysine analogues by hybrid computational and experimental approaches

Daniel Seeliger, Szabolcs Soeroes, Rebecca Klingberg, Dirk Schwarzer, Helmut Grubmüller*, Wolfgang Fischle

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

In cases where binding ligands of proteins are not easily available, structural analogues are often used. For example, in the analysis of proteins recognizing different methyl-lysine residues in histones, methyl-lysine analogues based on methyl-amino-alkylated cysteine residues have been introduced. Whether these are close enough to justify quantitative interpretation of binding experiments is however questionable. To systematically address this issue, we developed, applied, and assessed a hybrid computational/experimental approach that extracts the binding free energy difference between the native ligand (methyl-lysine) and the analogue (methyl-amino-alkylated cysteine) from a thermodynamic cycle. Our results indicate that measured and calculated binding differences are in very good agreement and therefore allow the correction of measured affinities of the analogues. We suggest that quantitative binding parameters for defined ligands in general can be derived by this method with remarkable accuracy.

Original languageEnglish (US)
Pages (from-to)150-154
Number of pages5
JournalACS Chemical Biology
Volume7
Issue number1
DOIs
StatePublished - Jan 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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