(511i) Insights into the Binding of ?-Wrapins to Amyloidogenic Proteins Using Simulations and Experiments
In our studies, we combine computational and experimental methods to gain biophysical insights into the binding and specificity of a series of Î²-wrapins in complex with the three disease-associated amyloidogenic proteins AÎ², Î±-syn, and IAPP. In our investigation of Î²-wrapins in complex with both AÎ² and Î±-syn, we identify the presence of common interactions between the current most promising dual, AÎ² and Î±-syn, binding Î²-wrapin AS10 and corresponding AÎ² / Î±-syn residues leading to dual-targeted properties, we depict the interactions which potentially act as switches diminishing the potency of Î²-wrapins for AÎ² or Î±-syn, and we provide insights into the binding of the current most active Î²-wrapin (ZSYM73 ) in complex with AÎ² , as well as the key role of polar electrostatic interactions contributing to an enhanced binding of Î²-wrapins to amyloidogenic proteins. We are currently investigating the interaction of Î²-wrapins with IAPP, and our preliminary results confirm our previous findings, and overall suggest that the use of computational association free energy calculations can be introduced to differentiate between active versus inactive engineered Î²-wrapins, as well as to identify the most active Î²-wrapins. We suggest that our studies can constitute the basis for the computational design of novel highly potent single or multi-targeted Î²-wrapin variants as potential therapeutics.
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