A soft penetrable sphere colloid model for the description of charge and excluded volume interactions in antibody solutions

Colloid models have frequently been used to successfully describe the influence of protein-protein interactions on antibody solution properties, but they suffer from inherent problems due to the anisotropic shape of the particles. The net charge required to describe electrostatic interactions is an effective quantity that cannot directly be obtained from the known molecular structure of an antibody, and the solution structure caused by excluded volume interactions is strongly overestimated at high concentrations due to the assumption of hard sphere interactions. As a result, these models have descriptive rather than predictive power. Here, we present an improved, soft penetrable sphere model based on analogies to soft colloids and star polyelectrolytes that takes into account the Y-shaped antibody form and the corresponding charge and ion distribution. The model not only correctly describes the concentration and ionic strength dependence of thermodynamic and collective dynamics quantities such as the osmotic compressibility and the apparent hydrodynamic radius, but also reproduces the center-of-mass static structure factor obtained in computer simulations using a weakly coarse-grained model, in which the antibody is described at an amino acid level. We demonstrate that this soft penetrable sphere model quantitatively reproduces experimental data from static and dynamic light scattering at low and high ionic strength for two well-characterized monoclonal antibodies (mAbs) when using the net charges and the overall mAb dimensions directly obtained from their molecular structure.