π‐π stacking interactions mediate molecular recognition between arginine and tryptophan containing peptides derived from human islet polypeptide

Abstract

AbstractCation‐π interactions, often found in protein assemblies, are characterized by favorable electrostatic interactions between an aromatic π‐electron surface and a positively charged species. There are evidences that reveal the importance of cation‐π interactions between arginine and aromatic residues in protein structure and function. In this paper, the effect of cation‐π interactions on the aggregation propensity of peptides derived from human islet polypeptide (hIAPP) was explored using UV resonance Raman and fluorescence spectroscopy. By employing an analog of hIAPP22–29 in which Phe‐23 is replaced with tryptophan (NWGAILSS), we were able to demonstrate an increase in the amyloidogenic propensity of this mutant in the presence of Zn2+ that is attributable to cation‐π interactions. In contrast, no cation‐π interactions were observed when the cationic F23R analog of hIAPP22–29 (NRGAILSS) was allowed to interact with NWGAILSS. From these observations, it was surmised that in these peptides, the dominant interaction between arginine and tryptophan involves the π‐cloud of the guanidino group and the indole ring, not cation‐π interactions. The spectroscopic data, supported by density functional theory‐based simulation results, suggest that arginine‐tryptophan interaction involves π‐π stacking where the guanidino group is oriented parallel to the indole ring. These hydrophobic interactions, coupled with the hydrotropic effect of the guanidine functionality of arginine, led to a delay in the aggregation kinetics of NWGAILSS. These unique interactions were further exploited to design a peptide inhibitor of full‐length amylin self‐assembly.