One-armed artificial receptors for the binding of polar tetrapeptides in water: probing the substrate selectivity of a combinatorial receptor library.
We have recently developed a new class of one-armed artificial receptors 1 for the binding of the polar tetrapeptide N-Ac-D-Glu-L-Lys-D-Ala-D-Ala-OH (EKAA) 2 in water using a combined combinatorial and statistical approach. We have now further probed the substrate selectivity of this receptor library 1 by screening a second tetrapeptide substrate (3) with the inverse sequence N-Ac-D-Ala-D-Ala-L-Lys-D-Glu-OH (AAKE). This "inverse" substrate is also efficiently bound by our receptors, with K(ass) approximately 6000 M(-1) for the best receptors, as determined both by a quantitative on-bead binding assay and by UV and fluorescence titration studies in free solution. Hence, the inverse tetrapeptide 3 is in general bound two to three times less efficiently than the "normal" peptide 2 (K(ass) approximately 17,000 M(-1)), even though the complexation mainly involves long-range electrostatic interactions and both the receptor and substrate are rather flexible. Molecular modeling and ab initio calculations have been used to rationalize the observed substrate selectivity and to analyze the various binding interactions within the complex.
Schmuck
Carsten
C
Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany. schmuck@chemie.uni-wuerzburg.de
Heil
Martin
M
D020650:Combinatorial Chemistry Techniques; D009842:Oligopeptides / Q000737:chemistry*; D019151:Peptide Library; D011487:Protein Conformation; D018000:Receptors, Peptide / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
C509028:N-Ac-D-Ala-D-Ala-L-Lys-D-Glu-OH; D009842:Oligopeptides; D019151:Peptide Library; D018000:Receptors, Peptide; D012996:Solutions; D014867:Water