“…Importantly, our MD simulations revealed that topological frustration is involved in up to 20% of the binding transitions (i.e., type II transition). Topological frustration has been observed in protein folding and binding, 27,[44][45][46][47][48][49][50][51] where backtracking of native contacts could occur at the initial stage as well as the late stage. In the eIF4G/eIF4E complex, wrapping of the two termini of eIF4G 391-490 without embracing the Nterminal tail of eIF4E after the initial docking leads to the formation of intermediates with incorrect topology.…”