On the Origin of the Stronger Binding of PIB over Thioflavin T to Protofibrils of the Alzheimer Amyloid-β Peptide: A Molecular Dynamics Study

Pittsburgh compound B (PIB) is a neutral derivative of the fluorescent dye Thioflavin T (ThT), which displays enhanced hydrophobicity and binding affinity to amyloid fibrils. We present molecular dynamics simulations of binding of PIB and ThT to a common cross-beta-subunit of the Alzheimer Amyloid-beta peptide (A beta). Our simulations of binding to A beta(9-40) protofibrils show that RIB, like ThT, selectively binds to the hydrophobic or aromatic surface grooves on the beta-sheet surface along the fibril axis. The lack of two methyl groups and charge in RIB not only improves its hydrophobicity but also leads to a deeper insertion of PIB compared to ThT into the surface grooves. This significantly increases the steric, aromatic, and hydrophobic interactions, and hence leads to stronger binding. Simulations on protofibrils consisting of the more-toxic A beta(17-42) revealed an additional binding mode in which RIB and ThT insert into the channel that forms in the loop region of the protofibril, sandwiched between two sheet layers. Our simulations indicate that the rotation between the two ring parts of the dyes is significantly more restricted when the dyes are bound to the surface of the cross-beta-subunits or to the channel inside the A beta(17-42) cross-beta-subunit, compared with free solution. The specific conformations of the dyes are influenced by small chemical modifications (ThT versus RIB) and by the environment in which the dye is placed.