Attractive protein−protein interactions in concentrated monoclonal antibody (mAb) solutions may lead to the formation of clusters that increase viscosity. Here, we propose an analytical model that relates mAb solution viscosity to clustering by accounting for the contributions of suboptimal mAb packing within a cluster and cluster fractal dimension. The influence of short-range, anisotropic attractions and longrange Coulombic repulsion on cluster properties is investigated by analyzing the clustersize distributions, cluster fractal dimensions, radial distribution functions, and static structure factors from a library of coarse-grained molecular dynamics simulations. The library spans a vast range of mAb charges and attractive interactions in solutions of varying ionic strength. We present a framework for combining the viscosity model and simulation library to successfully characterize the attraction, repulsion, and clustering of an experimental mAb in three different pH and cosolute conditions by fitting the measured viscosity or structure factor from small-angle X-ray scattering. At low ionic strength, the cluster-size distribution is impacted by strong charges, and both the viscosity and net charge or structure factor and net charge must be considered to deconvolute the effects of short-range attraction and long-range repulsion.

A systematic understanding of intermolecular interactions is necessary for designing concentrated monoclonal and polyclonal antibody solutions with reduced viscosity and enhanced stability. Here, we determine the effects of pH and cosolute on the strength and geometry of short-range anisotropic protein-protein attractions for a polyclonal bovine IgG by comparing intensities [I(q)] obtained from small-angle X-ray scattering to those computed in molecular dynamics simulations with 12-bead models. As our model embodies key features of the protein shape, it can describe the experimental I(q) for solutions of 10-200 mg/mL protein with only a small (<1 k B T) variation in the model's well depth. At high concentration, small changes in the interaction potential produce large increases in clustering given the close interprotein spacing. Reducing the pH below the pI or adding NaCl weakens short-range anisotropic attractions but not enough to remove large reversible oligomers that raise viscosity. In contrast, for arginine added at pH 5.5, a uniform attraction model is sufficient to describe the I(q) that plateaus at low q. With primarily monomers and dimers, the viscosity is reduced relative to the other systems that have larger clusters as described with a model that includes the cluster size distribution.