In order to optimize the conformation of RPC while keeping its warhead parts as close to that of the reference PROTAC conformation as possible, a constrained molecular mechanics optimization was then carried out. Here we employed the MacroModel module of Schrödinger software 28 to achieve the constrained minimization by imposing constraints on warhead atoms of RPC. The specific implementation, parameter setting and precautions can be found in supporting materials. After 200 iterations, the minimized RPC was saved as the optimized PROTAC conformation (OPC).