%0 Journal Article
%A Orr, Asuka A.
%A Shaykhalishahi, Hamed
%A Mirecka, Ewa A.
%A Jonnalagadda, Sai Vamshi R.
%A Hoyer, Wolfgang
%A Tamamis, Phanourios
%T Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of β-wrapins
%J Computers & chemical engineering
%V 116
%@ 0098-1354
%C Amsterdam [u.a.]
%I Elsevier Science
%M FZJ-2018-07289
%P 322 - 332
%D 2018
%X β-wrapins are engineered binding proteins stabilizing the β-hairpin conformations of amyloidogenic proteins islet amyloid polypeptide (IAPP), amyloid-β, and α-synuclein, thus inhibiting their amyloid propensity. Here, we use computational and experimental methods to investigate the molecular recognition of IAPP by β-wrapins. We show that the multi-targeted, IAPP, amyloid-β, and α-synuclein, binding properties of β-wrapins originate mainly from optimized interactions between β-wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Our results suggest that IAPP is a comparatively promiscuous β-wrapin target, probably due to the low number of charged residues in the IAPP β-hairpin motif. The sub-micromolar affinity of β-wrapin HI18, specifically selected against IAPP, is achieved in part by salt-bridge formation between HI18 residue Glu10 and the IAPP N-terminal 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30405276
%U <Go to ISI:>//WOS:000448410000023
%R 10.1016/j.compchemeng.2018.02.013
%U https://juser.fz-juelich.de/record/858403