Physics at the Biomolecular Interface: Fundamentals for Molecular Targeted Therapy PDF
Preview Physics at the Biomolecular Interface: Fundamentals for Molecular Targeted Therapy
Soft and Biological Matter Ariel Fernández Physics at the Biomolecular Interface Fundamentals for Molecular Targeted Therapy Soft and Biological Matter Serieseditors RobertoPiazza,Milano,Italy PeterSchall,Amsterdam,TheNetherlands RolandNetz,Berlin,Germany WenbingHu,Nanjing,China GerardWong,LosAngeles,USA PatrickSpicer,Sydney,Australia DavidAndelman,TelAviv,Israel ShigeyukiKomura,Tokyo,Japan Moreinformationabout thisseries athttp://www.springer.com/series/10783 “SoftandBiologicalMatter”isaseriesofauthoritativebookscoveringestablished andemergentareasintherealmofsoftmatterscience,includingbiologicalsystems spanningallrelevantlengthscalesfromthemoleculartothemesoscale.Itaimsto serve a broad interdisciplinary community of students and researchers in physics, chemistry,biophysicsandmaterialsscience. Pure research monographs in the series, as well as those of more pedagogical nature, will emphasize topics in fundamental physics, synthesis and design, char- acterizationandnewprospectiveapplicationsofsoftandbiologicalmattersystems. Theserieswillencompassexperimental,theoreticalandcomputationalapproaches. Topics in the scope of this series include but are not limited to: polymers, bio- polymers, polyelectrolytes, liquids, glasses, water, solutions, emulsions, foams, gels, ionic liquids, liquid crystals, colloids, granular matter, complex fluids, microfluidics,nanofluidics,membranesandinterfaces,activematter,cellmechan- icsandbiophysics. Bothauthoredandeditedvolumeswillbeconsidered. Ariel Ferna´ndez Physics at the Biomolecular Interface Fundamentals for Molecular Targeted Therapy ArielFerna´ndez NationalResearchCouncil(CONICET) BuenosAires,Argentina FormerHasselmannProfessorofEngineering RiceUniversity,USA ISSN2213-1736 ISSN2213-1744 (electronic) SoftandBiologicalMatter ISBN978-3-319-30851-7 ISBN978-3-319-30852-4 (eBook) DOI10.1007/978-3-319-30852-4 LibraryofCongressControlNumber:2016936663 ©SpringerInternationalPublishingSwitzerland2016 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexempt fromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthis book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained hereinorforanyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper ThisSpringerimprintispublishedbySpringerNature TheregisteredcompanyisSpringerInternationalPublishingAGSwitzerland Preface Whoevercannotseek theunforeseenseesnothing, fortheknownway isanimpasse. Heraclitus,sixthcenturyB.C. Thebiologicalfunctionalityofasolubleproteincanonlybefullygraspedwhenits aqueousinterfacebecomesanintegralpartofthestructuralanalysis.Furthermore,the acknowledgmentofhowexquisitelythestructureanddynamicsofproteinsandtheir aqueousenvironmentarerelatedatteststotheoverduerecognitionthatbiomolecular phenomena cannotbegrasped withoutdealing withinterfacialbehavioratmultiple scales.Thisisessentiallythedictumthatguidedthewritingofthisbook. The book focuses primarily on the biological and pharmacological role of interfacialforcesdeterminedbytheembeddingofproteinstructureinaphysiolog- icalaqueousenvironment.Byprovidingasuitablestatisticalmechanicalapparatus to handle epistructural (“around the structure”) interfacial phenomenology, the bookbecomesuniquelypositionedtoaddresscoreproblemsinmolecularbiophys- ics.Ithighlightstheimportanceofinterrelatedconceptslikewaterhydrogen-bond frustration,interfacialtensionandnon-Debyedielectricsindelineatingasolutionto the protein folding problem, in unraveling the physicochemical basis of enzyme catalysisandproteinassociations,indelineatingthemolecularetiologyofaberrant proteinaggregation,andinrationallydesigningmolecular-targetedtherapies. The book incrementally builds upon a statistical mechanical apparatus to deal withepistructuralinterfacesinabiologicalcontext.Asitextendspreviousworkin interfacialphysicstothebiologicalcontext,thebookstrivestomaintainthelevelof rigorexpectedfromaresearcherdevotedtointerfacialphysics,notwithstandingthe daunting complexitiesofbiomolecular systems. Inthe biological/biomedical con- text,thebookintroducesthenecessarycontrolsandexperimentalcorroborationsto validate the physical treatment. Furthermore, molecular dynamics and quantum v vi Preface mechanics computations are used to validate the theoretical advances. Such com- putationsfulfillthetenetsofstatisticalphysics. Grounded inrecentadvances inthe statistical mechanicsofepistructuralaque- ousinterfaces,thebookdevelopsatechnologicalplatformfordrugdesigntermed epistructure-baseddesign,aboveandbeyondtheprevailingparadigmofstructure- baseddrugdesign.Thebookissettoinspirescientistsatanylevelintheircareers determined to address some of the major challenges in molecular biophysics and pharmacological engineering. Thus, the book is essentially interdisciplinary and covers vast conceptual territory, from statistical physics to molecular-targeted therapy. As a measure of its intellectual latitude, Chap. 1 introduces a statistical thermodynamics framework to handle the aqueous interface of a protein, while Chap. 17 describes the epistructure-based design of kinase inhibitors with con- trolledmulti-targetactivitytotreatcancermetastasisandovercomedrugresistance. Inspiteofthisdiversity,theconceptualprogressionremainssmooththroughoutthe presentation. For this reason, the book can serve as a textbook, as originally intended, and also as an advanced monograph for practitioners in drug design or molecular-targetedtherapyinterestedinthetranslationalaspectsoftheirart.Fruit- ful reading requires a background in physical chemistry and some notions of biophysics. The selected problems at the end of the chapters and the progression inconceptualdifficultymakeitasuitabletextbookforagraduatelevelcourseoran elective course for seniors majoring in chemistry, physics, bioengineering, or relateddisciplines. BuenosAires,Argentina ArielFerna´ndez RiceUniversity,USA Contents 1 InterfacialPhysicsforWaterinBiology. . . . . . . . . . . . . . . . . . . . . 1 1.1 PhysicsoftheBiologicalInterface. . . . . . . . . . . . . . . . . . . . . . 1 1.2 WaterinBiology:AMolecularStare. . . . . . . . . . . . . . . . . . . . 3 1.3 InterfacialTensionofBiologicalWater. . . . . . . . . . . . . . . . . . 6 1.4 VariationalThermodynamicsfortheBiomolecular Interface. . . . . . . .. . . . . . . .. . . . . . . .. . . . . . . .. . . . . . . .. 10 1.5 TheAqueousInterfacefromaStructure-Centric Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.6 DehydronsPromoteProteinAssociations: AStructuralPerspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 1.7 EpistructuralPhysicsoftheProteinInterface. . . . . . . . . . . . . . 25 1.8 StatisticalMechanicsApparatusforDrug-Target Associations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 1.9 ThePrinciplesofEpistructuralPhysicsTranslate intotheArchitectureofSolubleProteins. . . . . . . . . . . . . . . . . 31 1.10 WhyEpistructuralPhysics?. . . . . . . . . . . . . . . . . . . . . . . . . . . 39 1.11 Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 2 DielectricStructureofAqueousInterfaces:FromClassical Non-DebyeElectrostaticstoaQuantumTheory ofInterfacialTension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 2.1 InterfacialTensionStoredasNon-DebyePolarization Energy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 2.2 Non-DebyeDielectricStructureoftheAqueous InterfaceforaSolubleProtein. . . . . . . . . . . . . . . . . . . . . . . . . 52 2.3 EpistructuralPhysicsRevealsaChemicalFunctionality fortheAqueousInterface. . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 2.4 PackingDefectsasCatalyticEnablers. . . . . . . . . . . . . . . . . . . 61 vii viii Contents 2.5 AQuantumTheoryofInterfacialTension andItsExperimentalVerification. . . . . . . . . . . . . . . . . . . . . . 63 2.6 Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 3 SolutiontotheProteinFoldingProblem. . . . . . . . . . . . . . . . . . . . . 71 3.1 ProteinFoldingasaMany-BodyProblem. . . . . . . . . . . . . . . . 72 3.2 CooperativityArisesfromHydrogen-BondWrapping. . . . . . . . 75 3.3 CooperativeFoldingPathways. . . . . . . . . . . . . . . . . . . . . . . . 78 3.4 ImprovingWrappingAlongFoldingPathways. . . . . . . . . . . . . 82 3.5 DielectricModulationbytheFoldingProtein. . . . . . . . . . . . . . 87 3.6 TheDehydronicFieldSteerstheFoldingProcess. . . . . . . . . . . 91 3.7 ThePrincipleofMinimalEpistructuralDistortion inProteinFolding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 3.8 BothStructuralandEpistructuralPerspectives AreNecessarytoSolvetheProteinFoldingProblem. . . . . . . . 99 3.9 DiscussionForum:TheFutileSearchforProteinFolding Intermediates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.10 Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 4 EpistructuralDynamicsofBiologicalWater. . . . . . . . . . . . . . . . . . 105 4.1 DynamicSingularitiesofBiomolecularInterfaces. . . . . . . . . . 105 4.2 DehydronsImpacttheDynamicsoftheAqueousInterface. . . . 107 4.3 De-wettingPropensitiesattheProtein-WaterInterface. . . . . . . 109 4.4 AqueousInterfaceasBlueprintforDrugDesign. . . . . . . . . . . . 113 4.5 Dehydron-HeatedInterfacialWater. . . . . . . . . . . . . . . . . . . . . 114 4.6 Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 5 Dehydron-RichProteinsintheOrder-Disorder TwilightZone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 5.1 DehydronClustersandtheOrder-DisorderTwilight. . . . . . . . . 122 5.2 SemiclassicalDielectricsatDehydron SitesontheAqueousInterface. . . . . . . . . . . . . . . . . . . . . . . . 124 5.3 SemiclassicalTreatmentofDielectricModulation ofInterfacialWaterAroundDehydrons. . . . . . . . . . . . . . . . . . 127 5.4 DielectricModulationbyDehydronsinthep53 DNA-BindingDomain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 5.5 ProteinswithDehydronClusters. . . . . . . . . . . . . . . . . . . . . . . 131 5.6 InferringDehydronsfromProteinSequence: Water-ExposedBackboneandDisorderPropensity. . . . . . . . . . 135 5.7 MisfoldingandAggregation:FlagrantViolation oftheArchitecturalGoldenRuleforProteinStructure. . . . . . . 139 5.8 Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Contents ix 6 DehydronasaMarkerforMolecularEvolution:Lessons fortheDrugDesigner. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 6.1 MolecularEvolutionfortheDrugDesigner. . . . . . . . . . . . . . . 152 6.2 DehydronPatternsAcrossOrthologousProteins: HallmarksofNon-adaptiveTraits. . . . . . . . . . . . . . . . . . . . . . 153 6.3 NaturalSelectionandDehydronPatterns. . . . . . . . . . . . . . . . . 155 6.4 InefficientSelectioninHumans:AnEpistructural ViewoftheCopingMechanism. . . . . . . . . . . . . . . . . . . . . . . 157 6.4.1 ExpressionPatternsSegregatingParalog Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 6.4.2 DehydronEnrichmentEnhancesDosage Imbalance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 6.5 HumanCapacitancetoCopewiththeImpactofDosage Imbalances. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 6.6 FitnessCatastrophesfortheHumanSpeciesAre theConsequenceofInteractomeComplexity. . . . . . . . . . . . . . 167 6.7 MolecularEvolutionaryInsightsfortheDrugDesigner: AnEpistructuralPerspective. . . . . . . . . . . . . . . . . . . . . . . . . . 170 6.8 Dehydron-BasedNon-adaptiveEvolutionary Technology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 6.9 DehydronRichnessAboveUnicellularLevels CreatesaStructuralDependenceExploitedtoEvolve Multicellularity. . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . 172 6.10 Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 7 CatalyticRoleofDehydronsinSolubleProteins: BiologicalChemistryofFrustratedInterfacialWater. . . . . . . . .. . 181 7.1 CatalyticDehydrons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 7.2 DehydronsasQuasi-ReactantsinBiologicalChemistry. . . . . . 186 7.3 TheDehydronasaCatalyticEngine. . . . . . . . . . . . . . . . . . . . 190 7.4 QuantumMechanicsofProtonTransferEvents InvolvingDehydrons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 7.5 QuantumMechanicalTreatmentoftheProtein-Water Interface. . . . . . . .. . . . . . . .. . . . . . . .. . . . . . . .. . . . . . . .. 192 7.6 DehydronChemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 7.7 Frustration-RelatedBiologicalChemistry. . . . . . . . . . . . . . . . . 201 7.8 Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 8 EpistructuralSelectivityFiltersforMolecular TargetedTherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 8.1 ControllingDrugSpecificity:ATherapeuticImperative. . . . . . 218 8.2 Epistructure-BasedDrugDesign. . . . . . . . . . . . . . . . . . . . . . . 222 8.3 PoorDehydronWrappersMakePoorDrugs. . . . . . . . . . . . . . . 225
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