beta-wrapins are engineered binding proteins stabilizing the beta-hairpin conformations of amyloidogenic proteins islet amyloid polypeptide (IAPP), amyloid-beta, and oz-synuclein, thus inhibiting their amyloid propensity. Here, we use computational and experimental methods to investigate the molecular recognition of IAPP by beta-wrapins. We show that the multi-targeted, IAPP, amyloid-beta and alpha-synuclein, binding properties of beta-wrapins originate mainly from optimized interactions between beta-wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Our results suggest that IAPP is a comparatively promiscuous beta-wrapin target, probably due to the low number of charged residues in the IAPP beta-hairpin motif. The sub-micromolar affinity of beta-wrapin HI18, specifically selected against IAPP, is achieved in part by salt-bridge formation between HI18 residue Glu10 and the IAPP Nterminal residue Lys1, both located in the flexible N-termini of the interacting proteins. Our findings provide insights towards developing novel protein-based single- or multi-targeted therapeutics. (C) 2018 The Authors. Published by Elsevier Ltd.