Direct Optical Detection of Aptamer Conformational Changes Induced by Target Molecules Oara Neumann, †,‡ Dongmao Zhang, § Felicia Tam, | Surbhi Lal, †,‡ Pernilla Wittung-Stafshede, ⊥ and Naomi J. Halas* ,†,‡,# Department of Electrical and Computer Engineering, Department of Chemistry, and Laboratory for Nanophotonics, Rice University, 6100 Main Street, Houston, Texas 77005, Department of Chemistry, Mississippi State University, Mississippi State, Mississippi 39762, Oxonica Materials, Inc., Mountain View, California 94043-4003, and Department of Chemistry, Umeå University, 901 87 Umeå, Sweden Aptamers are single-stranded DNA/RNA oligomers that fold into three-dimensional conformations in the presence of specific molecular targets. Surface-enhanced Raman spectroscopy (SERS) of thiol-bound DNA aptamer self- assembled monolayers on Au nanoshell surfaces provides a direct, label-free detection method for the interaction of DNA aptamers with target molecules. A spectral cross- correlation function, Γ, is shown to be a useful metric to quantify complex changes in the SERS spectra resulting from conformational changes in the aptamer induced by target analytes. While the pristine, unexposed anti-PDGF (PDGF ) platelet-derived growth factor) aptamer yields highly reproducible spectra with Γ ) 0.91 ( 0.01, following incubation with PDGF, the reproducibility of the SERS spectra is dramatically reduced, yielding Γ )0.67 ( 0.02. This approach also allows us to discriminate the response of a cocaine aptamer to its target from its weaker response to nonspecific analyte molecules. Aptamers are nucleic acid macromolecules of single-stranded DNA or RNA that can fold into three-dimensional complexes upon interaction with other molecules, providing preferential binding sites for molecular recognition of analytes. 1-3 Single-stranded DNA typically possesses a complex secondary structure due to many intramolecular base pairing opportunities, 4,5 which imparts increased stability to the folded complex. This provides a binding affinity in the picomolar to nanomolar range for highly target dependent aptamer-large molecule complexes, and in the mi- cromolar range for complexes formed with small molecules. 6-11 While numerous aptamer-based detection methods have been reported, 8-10,12-22 these techniques typically require complex labeling and sample preparation. The goal of direct optical detection of aptamer-target binding remains a key analytical challenge. 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