Electrostatic interactions are one of the key driving forces for protein-ligands complexation. Different levels for the theoretical modeling of such processes are available on the literature. Most of the studies on the Molecular Biology field are performed within numerical solutions of the Poisson-Boltzmann Equation and the dielectric continuum models framework. In such dielectric continuum models, there are two pivotal questions: (a) how the protein dielectric medium should be modeled, and (b) what protocol should be used when solving this effective Hamiltonian. By means of Monte Carlo (MC) and Poisson-Boltzmann (PB) calculations, we define the applicability of the PB approach with linear and nonlinear responses for macromolecular electrostatic interactions in electrolyte solution, revealing some physical mechanisms and limitations behind it especially due the raise of both macromolecular charge and concentration out of the strong coupling regime. A discrepancy between PB and MC for binding constant shifts is shown and explained in terms of the manner PB approximates the excess chemical potentials of the ligand, and not as a consequence of the nonlinear thermal treatment and/or explicit ion-ion interactions as it could be argued. Our findings also show that the nonlinear PB predictions with a low dielectric response well reproduce the pK shifts calculations carried out with an uniform dielectric model. This confirms and completes previous results obtained by both MC and linear PB calculations.