(426h) ?-Wrapin Proteins Sequestering Amyloidogenic Proteins: Understanding Their Function and Designing Novel ?-Wrapins with Improved Binding Affinities
We uncovered the binding and specificity of Î²-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 Î²-wrapinsâ affinity for AÎ²/Î±-syn5 as well as polar interactions leading to the high-affinity of ZSYM734 for AÎ²5, and suggest that IAPP is a comparatively promiscuous Î²-wrapin target6. Here, we present the binding of Î²-wrapins to IAPP. We show the sub-micromolar affinity of Î²-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 Î²-wrapins originate mainly from optimized interactions between Î²-wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties5,6. Furthermore, we computationally predict and experimentally validate the Î¼M affinities of Î²-wrapins ZAÎ²3 and AS69, specifically selected for AÎ² and Î±-syn, respectively, for IAPP, revealing their dual-binding properties.
Our studies show that we can use computational tools to predict Î²-wrapin affinity for amyloidogenic proteins providing a means to computationally design and evaluate Î²-wrapin variants. We are currently using the insights from our studies to design new Î²-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.
- Luheshi LM et al. PLoS Biol. 2007;8(3): e1000334.
- Mirecka EA et al. J Biotechnol. 2014;191:221-7.
- Mirecka EA et al. Angew Chem Int Ed Engl. 2014;53:4227-4230.
- Lindberg H et al. Biotechnol J. 2015;10(11):1707-18.
- Orr AA et al. J Phys Chem B. 2016;120(50):12781-12794.
- Orr AA et al. Comput Chem Eng. 2018;doi:10.1016/j.compchemeng.2018.02.013