Molecular recognition between biological entities is a remarkable feat that is required for life. Discovering molecular recognition scaffolds to disease markers and biowarfare targets poses a great challenge.{09}The potent combination of molecular recognition scaffolds and molecular display technology provide a rapid approach to discover ligands and receptors for new targets. A stochastic selection from diverse peptide and protein libraries can discover molecular recognition interactions to most targets. Improving molecular display approaches, such as phage display, can increase the probability of finding molecular recognition to targets. As described here, computational methods discovered and dissected the role DNA cross-hybridization can play in the success and failure of oligonucleotide-directed mutagenesis reactions for phage display library synthesis. DNA cross-hybridization diminishes the diversity of phage-displayed protein libraries by poisoning mutagenesis reactions. An increased understanding of cross-hybridization can guide mutagenesis design and synthesis to improve protein library diversities. Phage-displayed peptides recognizing the disease marker prostate-specific membrane antigen were isolated and combined with electrochemical impedance spectroscopy for sensitive biosensors.{09}This biosensor format could be applied to potentially any phage-displayed ligand. Non-specific background binding between phage particles and targets hinders selections for molecular recognition. The phage surface was modified to reduce non-specific binding to high pI proteins. Improving the phage display scaffold and library synthesis allows rapid discovery of molecular recognition scaffolds for biosensor applications.
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