2018
Bayesian analysis of isothermal titration calorimetry for binding thermodynamics
Nguyen T, Rustenburg A, Krimmer S, Zhang H, Clark J, Novick P, Branson K, Pande V, Chodera J, Minh D. Bayesian analysis of isothermal titration calorimetry for binding thermodynamics. PLOS ONE 2018, 13: e0203224. PMID: 30212471, PMCID: PMC6136728, DOI: 10.1371/journal.pone.0203224.Peer-Reviewed Original Research
2017
How Nothing Boosts Affinity: Hydrophobic Ligand Binding to the Virtually Vacated S1′ Pocket of Thermolysin
Krimmer S, Cramer J, Schiebel J, Heine A, Klebe G. How Nothing Boosts Affinity: Hydrophobic Ligand Binding to the Virtually Vacated S1′ Pocket of Thermolysin. Journal Of The American Chemical Society 2017, 139: 10419-10431. PMID: 28696673, DOI: 10.1021/jacs.7b05028.Peer-Reviewed Original ResearchConceptsWater moleculesPresent water moleculesWeak-binding ligandsAliphatic side chainsSpecificity pocketIsothermal titration calorimetrySolvent moleculesHigh-resolution crystallographyActive siteHydrophobic ligand bindingCrystalline stateElectron density mapsSide chainsTitration calorimetryS1 pocketNoble gas atomsSubstituentsThermodynamic signaturesFree energyHydration stateMoleculesLigandsPaying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors
Cramer J, Krimmer S, Heine A, Klebe G. Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors. Journal Of Medicinal Chemistry 2017, 60: 5791-5799. PMID: 28590130, DOI: 10.1021/acs.jmedchem.7b00490.Peer-Reviewed Original ResearchConceptsPolar groupsThermolysin inhibitorsProtein pocketFirst hydration shellProtein-ligand complexesProtein-solvent interfaceProspective binding sitesWater moleculesHydration shellSolvent effectsAmmonium groupsPartial desolvationSolvent-exposed positionsBinding thermodynamicsWater reorganizationThermodynamic fingerprintLead optimizationInhibitor scaffoldsHydrophobic analoguesDesolvationPharmacokinetic propertiesOpen pocket
2016
Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands
Krimmer S, Cramer J, Betz M, Fridh V, Karlsson R, Heine A, Klebe G. Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands. Journal Of Medicinal Chemistry 2016, 59: 10530-10548. PMID: 27933956, DOI: 10.1021/acs.jmedchem.6b00998.Peer-Reviewed Original ResearchConceptsDifferent hydrophobic substituentsKinetic binding profilesProtein-bound ligandsParent ligandSurface plasmon resonanceWater moleculesProtein-bound inhibitorThermolysin inhibitorsHigh-resolution crystallographyCongeneric seriesRational designWater networkMD simulationsHydrophobic substituentsPlasmon resonanceSubstituentsAffinity enhancementLigandsWater polygonsWater layerSurface water networkSurface water layerBinding signatureResidence timeCrystallographyImpact of Surface Water Layers on Protein–Ligand Binding: How Well Are Experimental Data Reproduced by Molecular Dynamics Simulations in a Thermolysin Test Case?
Betz M, Wulsdorf T, Krimmer S, Klebe G. Impact of Surface Water Layers on Protein–Ligand Binding: How Well Are Experimental Data Reproduced by Molecular Dynamics Simulations in a Thermolysin Test Case? Journal Of Chemical Information And Modeling 2016, 56: 223-233. PMID: 26691064, DOI: 10.1021/acs.jcim.5b00621.Peer-Reviewed Original ResearchConceptsObserved structure-activity relationshipsLocal water structureProtein-ligand bindingMolecular dynamics simulationsStructure-activity relationshipsHigh-resolution crystal structuresSolvation sitesWater structureSurface water networkWater rearrangementCrystal structureDesolvation effectsDifference electronMolecular dynamicsDynamics simulationsLigand portionWater networkDrug bindingContribution of waterWater layerComplexesSurface water layerWaterPhosphonamidatesStructure
2015
Thermodynamics of protein–ligand interactions as a reference for computational analysis: how to assess accuracy, reliability and relevance of experimental data
Krimmer S, Klebe G. Thermodynamics of protein–ligand interactions as a reference for computational analysis: how to assess accuracy, reliability and relevance of experimental data. Journal Of Computer-Aided Molecular Design 2015, 29: 867-883. PMID: 26376645, DOI: 10.1007/s10822-015-9867-y.Peer-Reviewed Original Research
2014
Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors
Krimmer S, Betz M, Heine A, Klebe G. Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors. ChemMedChem 2014, 9: 833-846. PMID: 24623396, DOI: 10.1002/cmdc.201400013.Peer-Reviewed Original ResearchConceptsWater moleculesFirst solvation layerThermodynamic binding profilesProtein-ligand binding processHigh-resolution crystal structuresIsothermal titration calorimetrySolvation patternsCorrelation of structureSolvation layerEntropy-driven bindingThermolysin inhibitorsCongeneric seriesSingle methyl groupCrystal structureWater arrangementSolvent-exposed surfaceTitration calorimetryBinding processMethyl groupS2 pocketSubstituentsComplex formationBinding propertiesLigand binding propertiesBiological systems