O2‐02‐05: RNA‐BINDING PROTEINS WITH MIXED CHARGE DOMAINS SELF‐ASSEMBLE AND AGGREGATE IN ALZHEIMER'S DISEASE

may accelerate or exacerbate disease pathogenesis. b-wrapin proteins were engineered to bind and sequester amyloidogenic monomers, and thus prohibit amyloid formation. ZAb3, the first reported b-wrapin sequesters a b-hairpin conformation of Ab, prohibiting aggregation of Ab monomers into toxic forms. b-wrapin variants have been engineered with varying activities for a-syn and IAPP, and ZSYM73, a b-wrapin with a pM affinity to Ab. Methods: Molecular dynamics simulations, free energy calculations, and surface plasmon resonance, among others enable us to uncover the binding and specificity of b-wrapins’ for the three amyloidogenic proteins. Results:Our studies reveal the key interactions acting as potential switches diminishing b-wrapins’ affinity for Ab/ a-syn, and suggest that IAPP is a comparatively promiscuous bwrapin target. We delineate the distinct role of energetic driving determinants leading to b-wrapin binding and specificity; while both nonpolar and polar interactions synergistically contribute to binding, the polar binding energy component is the key energetic determinant contributing to b-wrapins’ high-affinity. In line with this, our studies show that the high-affinity of ZSYM73 is attributed to salt-bridges stabilizing the ZSYM73:Ab complex. Additionally we show that multi-targeted binding properties of b-wrapins originate mainly from optimized interactions between b-wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Conclusions: Computational tools allow us to predict b-wrapin affinity for amyloidogenic proteins.We are currently using the insights fromour studies to design new b-wrapinswith improved affinities for one or combinations of the amyloidogenic proteins, which may constitute a promising and efficient direction for the future treatment of Alzheimer’s disease in place of molecules binding to Ab only. 1. Luo J et al. J Biol Chem. 2016;291(32):16485-93. 2. Luheshi LM et al. PLoS Biol. 2007;8(3): e1000334. 3. Hoyer W, H€ard T. J Mol Biol. 2008;378:398-411. 4. Mirecka EA et al. J Biotechnol. 2014;191:221-7. 5. Shaykhalishahi H et al. Chembiochem. 2015;16:411-414. 6.Mirecka EAet al. Angew Chem Int Ed Engl. 2014;53:4227-4230. 7. Lindberg H et al. Biotechnol J. 2015;10(11):1707-18. 8. Orr AA et al. J Phys Chem B. 2016;120(50):12781-12794.