Investigation of the Interactions of b-Peptides with DNA Duplexes by Circular Dichroism Spectroscopy 1 ) by Kenji Namoto 2 ), James Gardiner 3 ), Thierry Kimmerlin 4 ), and Dieter Seebach* Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, Eidgençssische Technische Hochschule, ETH-Zürich, Hçnggerberg, HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich (phone: + 41446322990;fax: + 41446321144; e-mail: seebach@org.chem.ethz.ch) Dedicated to Professor Helgard Raubenheimer, University of Stellenbosch, on the occasion of his 65th birthday. The interaction of b-peptides with the DNA duplexes of dA 20 dT 20 and a GCN4-binding CRE sequence was examined. To gauge the factors that govern these interactions, two b-pentadecapeptides, 1 and 2,a b-dodecapeptide, 3,three b-decapeptides, 4 – 6,three b-heptapeptides, 7 – 9,and b-octaarginine 10 weredesignedandsynthesized.The b-peptideswereconceivedtoadopta b-peptide 3 14 helix,inwhich thesidechainsatposition i and i + 3arealignedverticallyalongonesideofthehelix.Thesidechainsof Lys,Asn,andArgwerepositionedsuchthatpotentialH-bondingsiteswerecreatedforahelicalconfor- mation to interact with the base pairs of DNA. CD Analysis showed that b-peptides 1, 2, and 10 inter- acted with dA 20 dT 20 . In addition, b-peptides 1 and 2 showed significant interaction with a DNA-duplex 20mer containing the ATF/CREB recognition sequence for the regulatory protein GCN4. It is impossi- ble,atthisstageoftheinvestigation,tomakeasafeproposalabouttheactualnatureoftheinteractionof the structures(s) of the complexes, the formation of which is suggested by the CD spectra reported herein. 1. Introduction. –TheinteractionofpeptidesandproteinswithDNAisfundamen- taltothechemistryoflife[2],and,assuch,hasdominatedthecontemporarysceneof modern molecular sciences. Crucial processes such as DNA replication, restoration, compaction,transcription,anddegradationareallregulatedbyproteinscapableofrec- ognizing,andtherebycomplexingwith,theDNAdoublehelix[3].ManyDNA-binding proteins contain ordered structures that lead to selective recognition and binding of specific DNA sequences. Examples of such structures include the zinc-finger, the leu- cine zipper, and the helix–turn–helix, terms now familiar in biochemistry and protein 1 ) Part of the results described herein was mentioned in a preliminary communication [1]. 2 ) PostdoctoralFellowatETHZürich,2002–2004, financed by Novartis Pharma AG andbythe Swiss National Science Foundation, Project No. 200-058831.99. Present address: Novartis Pharma AG, NIBR, CH-4002 Basel. 3 ) PostdoctoralFellowatETH,2004–2007,financedbythe New Zealand Foundation for Research Sci- ence and Technology , Project No. SWSS0401. 4 ) PartoftheETHdissertationNo.15800.Presentaddress: Novartis Institutes for Biomedical Research GmbH & Co KG, A-1235 Vienna. # 2006 Verlag Helvetica Chimica Acta AG, Zürich Helvetica Chimica Acta –Vol.89(2006) 3087