You need to decide at which pH you want to perform your simulation, and adjust the protonation states of your molecules accordingly.

First be clear what the different terms mean, as the way you posed your question indicates some confusion: Each titratable group in your system has a pKa value dependent on its chemical makeup and its environment. These pKa values determine to what extent this group will be protonated at a given pH (negative logarithm of the H+ concentration in the solution), and this in turn will determine the charge distribution in the molecules, and therefore influence the electrostatic forces in your system.

Dear Annemarie Honegger,

Thank you for the support, it's very very helpful! I was suggested to use the H++ web to "set" desired pH which automatically changed the protonation states, and everything could be done within one to two clicks. It was too convenient that I did not think of the mechanism. I will dig into the theory then!

Regards

Some additional considerations: (1) calculate also pKa for the ligand; (2) local environment may affect pKa (this is true for both the protein and the ligand); (3) if the net charge of the system is too large, it may be convenient to use neutral forms of ionizable residues located far from the region of interest to avoid having to add too many counterions.