Combining conformational sampling and selection to identify the binding mode of zinc-bound amyloid peptides with bifunctional molecules
The pathogenesis of Alzheimer's disease (AD) has been suggested to be related with the aggregation of amyloid beta (A beta) peptides. Metal ions (e.g. Cu, Fe, and Zn) are supposed to induce the aggregation of A beta. Recent development of bifunctional molecules that are capable of interacting with A beta and chelating biometal ions provides promising therapeutics to AD. However, the molecular mechanism for how A beta, metal ions, and bifunctional molecules interact with each other is still elusive. In this study, the binding mode of Zn2+-bound A beta with bifunctional molecules was investigated by the combination of conformational sampling of full-length A beta peptides using replica exchange molecular dynamics simulations (REMD) and conformational selection using molecular docking and classical MD simulations. We demonstrate that Zn2+-bound A beta((1-40)) and A beta((1-42)) exhibit different conformational ensemble. Both A beta peptides can adopt various conformations to recognize typical bifunctional molecules with different binding affinities. The bifunctional molecules exhibit their dual functions by first preferentially interfering with hydrophobic residues 17-21 and/or 30-35 of Zn2+-bound A beta. Additional interactions with residues surrounding Zn2+ could possibly disrupt interactions between Zn2+ and A beta, which then facilitate these small molecules to chelate Zn2+. The binding free energy calculations further demonstrate that the association of A beta with bifunctional molecules is driven by enthalpy. Our results provide a feasible approach to understand the recognition mechanism of disordered proteins with small molecules, which could be helpful to the design of novel AD drugs.
amyloid bifunctional molecules alzheimer's disease metal ions replica exchange molecular dynamics simulations