(426h) ?-Wrapin Proteins Sequestering Amyloidogenic Proteins: Understanding Their Function and Designing Novel ?-Wrapins with Improved Binding Affinities
AIChE Annual Meeting
2018
2018 AIChE Annual Meeting
Engineering Sciences and Fundamentals
Thermodynamics of Biomolecular Folding and Assembly
Tuesday, October 30, 2018 - 5:15pm to 5:30pm
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-wrapinsâ 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, Alzheimerâs disease, and Parkinsonâs disease.
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