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Abstract
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Design of peptide affinity ligands against biological targets is important for a broad range of applications. Here, we report on de novo and combinatorial strategies for the design of high-affinity and high-specificity peptides against S-protein as a target. The peptide libraries employed in this study contain (1) consensus motif (CM) sequences identified from high-throughput phage combinatorial screening, (2) point mutations of CM sequences, and (3) de novo sequences rationally designed based on stereo-chemical information of the complex between S-protein and its natural ligand, S-peptide. In general, point mutations to CM allowed for modulating peptide affinity and specificity over a broad range. This is particularly useful in designing peptides with varying affinities and specificities for the target. De novo sequences, especially those based on the S-protein binding pocket, on average bound with higher affinities within a narrow range (10-100 nM) as compared to point mutations to CM (1 nM-2 ...M). As such, the approaches described here serve as a general guide for optimizing the design of peptide affinity ligands for a wide range of target proteins or applications.[PUBLICATION ABSTRACT]