Nucleic Acid–Metal Ion Interactions RSC Biomolecular Sciences Editorial Board: ProfessorStephenNeidle(Chairman),TheSchoolofPharmacy,UniversityofLondon,UK DrSimonFCampbellCBE,FRS DrMariusClore,NationalInstitutesofHealth,USA ProfessorDavidMJLilleyFRS,UniversityofDundee,UK ThisSeriesisdevotedtocoverageofthe interfacebetweenthe chemicalandbiological sciences, especially structural biology, chemical biology, bio- and chemo-informatics, drug discovery and development,chemicalenzymologyandbiophysicalchemistry.Idealasreferenceandstate-of-the- artguidesatthegraduateandpost-graduatelevel. Titles in the Series: BiophysicalandStructuralAspectsofBioenergetics EditedbyMa˚rtenWikstro¨m,UniversityofHelsinki,Finland ComputationalandStructuralApproachestoDrugDiscovery:Ligand–ProteinInteractions EditedbyRobertMStroudandJanetFiner-Moore,UniversityofCaliforniainSanFrancisco,San Francisco,CA,USA ExploitingChemicalDiversityforDrugDiscovery EditedbyPaulA.Bartlett,DepartmentofChemistry,UniversityofCalifornia,Berkeley,USAand MichaelEntzeroth,S*BioPteLtd,Singapore Metabolomics,MetabonomicsandMetaboliteProfiling EditedbyWilliamJ.Griffiths,UniversityofLondon,TheSchoolofPharmacy,UniversityofLondon, London,UK NucleicAcid–MetalIonInteractions EditedbyNicholasV.Hud,SchoolofChemistryandBiochemistry,GeorgiaInstituteofTechnology, Atlanta,GA,USA Protein–CarbohydrateInteractionsinInfectiousDisease EditedbyCaroleA.Bewley,NationalInstitutesofHealth,Bethesda,Maryland,USA ProteinFolding,MisfoldingandAggregation:ClassicalThemesandNovelApproaches EditedbyVictorMun˜oz,DepartmentofChemistryandBiochemistry,UniversityofMaryland,MD, USA Protein-NucleicAcidInteractions:StructuralBiology Edited by Phoebe A. Rice, Department of Biochemistry & Molecular Biology, The University of Chicago, Chicago IL, USA and Carl C. Correll, Dept of Biochemistry and Molecular Biology, RosalindFranklinUniversity,NorthChicago,IL,USA QuadruplexNucleicAcids EditedbyStephenNeidle,TheSchoolofPharmacy,UniversityofLondon,London,UKandShankar Balasubramanian,DepartmentofChemistry,UniversityofCambridge,Cambridge,UK RibozymesandRNACatalysis Edited by David MJ Lilley FRS, University of Dundee, Dundee, UK and Fritz Eckstein, Max- Planck-InstitutforExperimentalMedicine,Goettingen,Germany Sequence-specificDNABindingAgents EditedbyMichaelWaring,DepartmentofPharmacology,UniversityofCambridge,Cambridge,UK StructuralBiologyofMembraneProteins Edited by Reinhard Grisshammer and Susan K. Buchanan, Laboratory of Molecular Biology, NationalInstitutesofHealth,Bethesda,Maryland,USA Structure-basedDrugDiscovery:AnOverview EditedbyRoderickE.Hubbard,UniversityofYork,UKandVernalis(R&D)Ltd,Cambridge,UK TherapeuticOligonucleotides Edited by Jens Kurreck, Institutefor Chemistryand Biochemistry, Free University Berlin,Berlin, Germany Visitourwebsiteatwww.rsc.org/biomolecularsciences Forfurtherinformationpleasecontact: SalesandCustomerCare,RoyalSocietyofChemistry,ThomasGrahamHouse, SciencePark,MiltonRoad,Cambridge,CB40WF,UK Telephone:+44(0)1223432360,Fax:+44(0)1223426017,Email:[email protected] Nucleic Acid–Metal Ion Interactions Edited by Nicholas V. Hud School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA ISBN: 978-0-85404-195-4 AcataloguerecordforthisbookisavailablefromtheBritishLibrary rRoyalSocietyofChemistry2009 Allrightsreserved Apart from fair dealing for the purposes of research for non-commercial purposes or for privatestudy,criticismorreview,aspermittedundertheCopyright,DesignsandPatents Act1988andtheCopyrightandRelatedRightsRegulations2003,thispublicationmaynot be reproduced, stored or transmitted, in any form or by any means, without the prior permissioninwritingofTheRoyalSocietyofChemistryorthecopyrightowner,orinthe case of reproduction in accordance with the terms of licences issued by the Copyright LicensingAgencyintheUK,orinaccordancewiththetermsofthelicencesissuedbythe appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistryattheaddressprintedonthispage. PublishedbyTheRoyalSocietyofChemistry, ThomasGrahamHouse,SciencePark,MiltonRoad, CambridgeCB40WF,UK RegisteredCharityNumber207890 Forfurtherinformationseeourwebsiteatwww.rsc.org Preface Natural biochemical processes are continuously being discovered that involve RNA. Some of these processes, such as RNA interference, are now being exploitedforbiotechnologyandmedicinalapplications.DNAhasalsoproven in recent years to be more than a passive storehouse of information. For example, non-B-form DNA structures formed by G-rich DNA have been shown to participate in the regulation of gene expression, a discovery that presents new possibilities for drug targets in the genome. The current quest to understandhownucleicacidsfunctionatthemostfundamentallevelsrequires that we have a detailed understanding of nucleic acid–metal ion interactions. Due to thepolyanionic nature ofnucleic acids, DNA and RNA molecules are alwaysassociatedwithcationsinlivingcellsandthesecationsareessentialfor maintaining nucleic acid structure and function. The nature of these inter- actions varies greatly, from monovalent alkali metal ions that are primarily delocalized in a diffuse cloud around duplex DNA and RNA, to transition metals that are directly coordinated to the nucleotide bases. During the past decade, manyimportant insightsregardingnucleicacid–metal ioninteractions have resulted from the application of spectroscopic techniques in the solution stateandthedeterminationofX-raycrystalstructures.Thepresentvolumehas been compiled to provide readers with an overview of these biophysical investigations. Our goal in writing each chapter has been two-fold. We have soughttoproduceabookthatcouldserveasareferencesourceforresearchers in the field, and also a text with sufficient background to serve as an initial starting point for students and researchers interested in entering the field or simply learning about this exciting topic. As Editor, I am indebted to my co-authors for their generous contributions tothisbook.Wehaveworkedtogethertomakethechaptersascomplementary as possible and to minimize overlap. RSCBiomolecularSciences NucleicAcid–MetalIonInteractions EditedbyNicholasV.Hud rRoyalSocietyofChemistry2009 PublishedbytheRoyalSocietyofChemistry,www.rsc.org v Contents Chapter 1 Complexes of Nucleic Acids with Group I and II Cations Chiaolong Hsiao, Emmanuel Tannenbaum, Halena VanDeusen, Eli Hershkovitz, Ginger Perng, Allen R. Tannenbaum and Loren Dean Williams 1.1 Introduction 1 1.1.1 Modern Treasure Troves of Structural Information: Large RNAs 2 1.2 Nucleic Acid Folding 2 1.2.1 Cations 2 1.2.2 The RNA Folding Hierarchy 3 1.2.3 Alternative RNA Folding Hierarchies 4 1.3 Coordination Chemistry 4 1.3.1 Group I 4 1.3.2 Group II 7 1.4 Experimental Methods for Determination of Cation Positions in X-ray Structures 24 1.4.1 Group I 24 1.4.2 Group II 25 1.5 The Two Binding-mode Formalism 25 1.5.1 Thermodynamic/Kinetic Definition 25 1.5.2 Structural Definition 26 1.5.3 Computational Definition 26 1.5.4 Breaking the Two Binding-mode Formalism 27 1.6 Reaction Coordinates for RNA Folding 27 1.6.1 The Utility of 3D Databases for Determining Mechanism 27 RSCBiomolecularSciences NucleicAcid–MetalIonInteractions EditedbyNicholasV.Hud rRoyalSocietyofChemistry2009 PublishedbytheRoyalSocietyofChemistry,www.rsc.org vii viii Contents 1.6.2 Mg21–RNA Complexes Report on Folding Intermediates 28 Appendix 28 Acknowledgements 32 References 32 Chapter 2 Coordinative Bond Formation Between Metal Ions and Nucleic Acid Bases Bernhard Lippert 2.1 Introduction 39 2.1.1 Nucleic Acids and Metal Ions 39 2.1.2 Types of Interactions 40 2.1.3 Brief History 41 2.1.4 Scope 42 2.2 Nucleobases as Ligands 42 2.2.1 Location of Donor Sites in DNA and RNAs 42 2.2.2 Acid–Base Equilibria of Nucleobases 43 2.2.3 ‘Conventional’MetalBindingSitesinNeutral Nucleobases 44 2.2.4 Exocyclic Amino Groups: Not Used Unless Deprotonated 45 2.2.5 Metal Coordination to Rare Nucleobase Tautomers 46 2.2.6 Deprotonated Nucleobases 48 2.2.7 Organometallic Nucleobase Complexes 50 2.2.8 Chelates, Macrochelates and ‘Indirect’ Chelates 52 2.2.9 Coordination Behavior of Di- and Multinuclear Metal Complexes 52 2.2.10 Protonated Purine Bases as Ligands 54 2.2.11 Other Modes 54 2.2.12 Metal Migration 54 2.2.13 Metals as Chameleons in Nucleic Acid Coordination 54 2.2.14 Complex Stabilities 55 2.3 Consequences of Metal Coordination 57 2.3.1 Cross-link Formation in dsDNA 57 2.3.2 Multistranded Nucleic Acids 59 2.3.3 Subtle Effects of Metal Coordination 62 2.3.4 Irreversible Alterations 66 2.4 Summary and Outlook 68 References 69 Contents ix Chapter 3 Sequence-specific DNA–Metal Ion Interactions Nicholas V. Hud and Aaron E. Engelhart 3.1 Introduction 75 3.2 A Brief Overview of Cation Binding Modes to DNA 77 3.3 Defining A-tracts, G-tracts and Generic DNA 79 3.4 Divalent Cation Localization 79 3.4.1 Divalent Cations and the Major Groove 79 3.4.2 Divalent Cations and the Minor Groove 86 3.5 Monovalent Cation Localization 92 3.5.1 Monovalent Cations and the Major Groove 92 3.5.2 Monovalent Cations and the Minor Groove 96 3.6 Testing Cation Size Selection of the A-tract Minor Groove Using a Large Monovalent Cation 103 3.7 Additional Experimental Evidence of Sequence-specific Binding of Cations to DNA 104 3.7.1 Capillary Electrophoresis 104 3.7.2 Hydration Measurements 104 3.8 Sequence-specific Cation Localization and DNA Fine Structure 106 3.9 Investigations of the Role of Cations in DNA Fine Structure Using Non-natural Bases 110 3.10 Conclusions and Perspectives 112 Acknowledgements 112 References 112 Chapter 4 Metal Ion Interactions with G-Quadruplex Structures Aaron E. Engelhart, Janez Plavec, O¨zgu¨l Persil and Nicholas V. Hud 4.1 Introduction 118 4.2 A Brief Overview of G-quadruplex Structures and Folding Topologies 121 4.3 X-ray Crystallographic Studies of Cation Coordination by G-quadruplexes 123 4.3.1 X-ray Studies of Monovalent Cation Coordination 123 4.3.2 X-ray Studies of Divalent Cation Coordination 128 4.4 NMR Studies of Cation Coordination by G-quadruplexes 130 4.4.1 Solution-state NMR Studies of Monovalent Cation Coordination 130