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Position dependent mismatch discrimination on DNA microarrays – experiments and model

DOI: 10.1186/1471-2105-9-509

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Abstract:

We observe that mismatch discrimination is mostly determined by the defect position (relative to the duplex ends) as well as by the sequence context. We investigate the thermodynamics of the oligonucleotide duplexes on the basis of double-ended molecular zipper. Theoretical predictions of defect positional influence as well as long range sequence influence agree well with the experimental results.Molecular zipping at thermodynamic equilibrium explains the binding affinity of mismatched DNA duplexes on microarrays well. The position dependent nearest neighbor model (PDNN) can be inferred from it. Quantitative understanding of microarray experiments from first principles is in reach.The well-known double-helix structure of nucleic acids results from sequence-specific binding between complementary single strands. Sequential base pairing between A·T and C·G base pairs along the two complementary strands results in the formation of stable duplexes. This so called hybridization process is fundamental to many biological processes and biotechnologies. Microarrays consist of surface-tethered probe sequences, which act as specific scavengers for their respective complementary target sequence. The molecular recognition enables a highly parallel detection of nucleic acid sequences in complex target mixtures. Hybridization also occurs with single mismatched (MM) base pairs, however, these duplexes are significantly less stable than the corresponding perfect match (PM) [1,2]. The single base pair mismatch-discrimination capability of short (~20 nt) oligonucleotide probes provides an important diagnostic tool for the detection of point-mutations and single nucleotide polymorphisms (SNPs) [3]. DNA duplex stability arises from hydrogen bonding and base stacking interactions (the latter comprise van der Waals interactions, electrostatic and hydrophobic interactions between adjacent base pairs). According to the well-established nearest-neighbor model, thermodynamically a nucleic acid

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