title: Quantitative assessment of protein interaction with methyl-lysine analogues by hybrid computational and experimental approaches.
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.
authors: Daniel
authors: D
authors: Seeliger
authors: Szabolcs
authors: S
authors: Soeroes
authors: Rebecca
authors: R
authors: Klingberg
authors: Dirk
authors: D
authors: Schwarzer
authors: Helmut
authors: H
authors: Grubmüller
authors: Wolfgang
authors: W
authors: Fischle
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli; D008024:Ligands; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D008024:Ligands; D010455:Peptides; D011994:Recombinant Proteins; D008239:Lysine; D003545:Cysteine