(426h) ?-Wrapin Proteins Sequestering Amyloidogenic Proteins: Understanding Their Function and Designing Novel ?-Wrapins with Improved Binding Affinities | AIChE

(426h) ?-Wrapin Proteins Sequestering Amyloidogenic Proteins: Understanding Their Function and Designing Novel ?-Wrapins with Improved Binding Affinities


Tamamis, P. - Presenter, Texas A&M University
Jonnalagadda, S. V. R., Texas A&M University
Hoyer, W., Heinrich-Heine-Universita? Düsseldorf
Orr, A. A., Texas A&M University
Amyloidogenic proteins aggregate into β-sheet-rich amyloid fibrils associated with several age related diseases. Pancreatic islet amyloids formed by islet amyloid polypeptide (IAPP), senile plaques formed by amyloid-β (Aβ), and Lewy bodies formed by α-synuclein (α-syn) are pathological features of types II diabetes, Alzheimer’s disease, and Parkinson’s disease, respectively. β-wrapin proteins are engineered binding proteins that stabilize the β-hairpin conformations of amyloidogenic protein monomers, thus inhibiting their amyloid propensity and toxicity. β-wrapin variants have been engineered with varying activities for α-syn and IAPP1-4. Notably, β-wrapin variant, ZSYM73, was recently engineered with a pM affinity to Aβ4.

We uncovered the binding and specificity of β-wrapins for the three amyloidogenic proteins using molecular dynamics simulations, free energy calculations, and surface plasmon resonance, among others5,6. Our studies revealed the key interactions acting as potential switches diminishing β-wrapins’ affinity for Aβ/α-syn5 as well as polar interactions leading to the high-affinity of ZSYM734 for Aβ5, and suggest that IAPP is a comparatively promiscuous β-wrapin target6. Here, we present the binding of β-wrapins to IAPP. We show the sub-micromolar affinity of β-wrapin HI183 for IAPP is attributed to a salt-bridge between the flexible N-termini of the interacting proteins6. Additionally, we showed that multi-targeted 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 properties5,6. Furthermore, we computationally predict and experimentally validate the μM affinities of β-wrapins ZAβ3 and AS69, specifically selected for Aβ and α-syn, respectively, for IAPP, revealing their dual-binding properties.

Our studies show that we can use computational tools to predict β-wrapin affinity for amyloidogenic proteins providing a means to computationally design and evaluate β-wrapin variants. We are currently using the insights from our studies to design new β-wrapins with improved affinities for the amyloidogenic proteins through computational optimization-based design, MD simulations, and energy calculations, which may constitute a promising and efficient direction for the future treatment of type II diabetes, Alzheimer’s disease, and Parkinson’s disease.

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