Models for binding cooperativities of inhibitors with transthyretin.

Here, molecular dynamics (MD) simulations are performed to study the differences of binding channel shapes of TTR with two inhibitors, flufenamic acid (FLU) and one kind of N-phenyl phenoxazine (BPD). The asymmetries of global structure including the central binding channel are found to be intrinsic. Moreover, the conformational changes of the binding channel are responsible for negative cooperativity (NC) or independent cooperativity (IC) of ligands. The results suggested a possible binding mechanism addressing NC of FLU and IC of BPD. For FLU, when the first ligand binds with TTR, it leads to expansion of the second binding site which may weaken the interaction of the second FLU with TTR. But for BPD, the first ligand's binding changes the second site's shape slightly, the second ligand has similar binding ability with TTR in the second site like the first binding event.