The DIIS method 55-57 was utilized to optimize the wave function during the selfconsistent field (SCF) process. A convergence threshold was set to 1•10 -5 au with respect to the largest component of the electronic gradient. In order to accelerate convergence, the initial wave function guess in each MD step is based on an extrapolation from the preceding five steps. 58 A Born-Oppenheimer (BO), QM/MM MD equilibration run was performed in the NVT ensemble for 5 ps corresponding to 10,000 steps using a time step of 0.48 fs (20.0 a.u.) The temperature was maintained at 303.15 K using the Berendensen thermostat on the nuclear positions and a time constant of 5000 a.u. After, we continued with an NVT but using four separate Nose-Hoover thermostats, 59-61 each having its own chain and a frequency of 5000 cm -1 : i) the QM subsystem, ii) the membrane, iii) the protein and iv) water and ions. This simulation was run for 45 ps.