After proper system setup, the target complexes were subjected to minimization in two steps to remove the poor contacts during system setup. In the first step, only water molecules were minimized while in the second step entire complex was minimized using 5000 steps of steepest descent and subsequently 5000 of conjugate gradient algorithm. Afterward, the systems were gently heated from 10 to 300 K using an NVT ensemble for 50 ps. Following that, we normalized the system under NPT ensemble for 1 ns at a target temperature and pressure of 300 K and 1.0 atm using the Langevin thermostat and Berendsen barostat respectively. Along with that, 2 ps of collision frequency was also applied where the pressure relaxation time was 1 ps. Systems were then equilibrated for the next ~3 ns at the same conditions. The equilibrated systems underwent a further productive MD run of at least 100 ns (depending on the system) using a multi-trajectory approach in which we restarted the simulation after completion of each 50 ns of simulation at a random velocity. The algorithms SHAKE and particle mesh Ewald (PME) were used to constrain the hydrogen bonds and treat the long-range electrostatic forces, respectively. All MD simulations were carried out in the GPU version of the AMBER20 package 32 .