title: Design of peptide affinity ligands for S-protein: a comparison of combinatorial and de novo design strategies.
abstract: 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 μM). 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.
authors.affiliation: The Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Chandra
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrison
authors.forename: James
authors.initials: J
authors.lastname: Woo
authors.forename: Steven
authors.initials: S
authors.lastname: Cramer
authors.forename: Pankaj
authors.initials: P
authors.lastname: Karande
mesh_terms: D000345:Affinity Labels / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D020650:Combinatorial Chemistry Techniques; D016384:Consensus Sequence; D018360:Crystallography, X-Ray; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D017354:Point Mutation; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D012260:Ribonucleases / Q000737:chemistry* / Q000235:genetics
chemical_list: D000345:Affinity Labels; D008024:Ligands; D010446:Peptide Fragments; D019151:Peptide Library; D010455:Peptides; C023560:ribonuclease S-peptide; D012260:Ribonucleases