Predicting Experimental Values and the Effects of Histidine Charge States for Monoclonal Antibodies Using Coarse-Grained Molecular Simulations.

Static light scattering (SLS) was used to characterize five monoclonal antibodies (MAbs) as a function of total ionic strength (TIS) at pH values between 5.5 and 7.0. Second osmotic virial coefficient () values were determined experimentally for each MAb as a function of TIS using low protein concentration SLS data. Coarse-grained molecular simulations were performed to predict the values for each MAb at a given pH and TIS. To include the effect of charge fluctuations of titratable residues in the calculations, a statistical approach was introduced in the Monte Carlo algorithm based on the protonation probability based on a given pH value and the Henderson-Hasselbalch equation. The charged residues were allowed to fluctuate individually, based on the sampled microstates and the influence of electrostatic interactions on net protein-protein interactions during the simulations. Compared to static charge simulations, the new approach provided improved results compared to experimental values at pH conditions near the p of titratable residues.