Physics-based surface patch analysis for prediction of hydrophobic contribution to viscosity of mAbs

The viscosity of monoclonal antibody solutions is critical in their biopharmaceutical application, as it directly influences the ease of subcutaneous injection. Although many descriptors have been developed to enable the in silico prediction of viscosity, they are typically based on electrostatic properties while neglecting hydrophobicity, or rely on AI-based approaches with limited generalizability, both rendering the models inadequate. Moreover, the scarcity of high-quality experimental datasets further limits the use of machine learning algorithms, necessitating interpretable analysis of protein–protein interactions. In this work, we combine computational modeling with experimental viscosity measurements for a set of monoclonal antibodies. We introduce an algorithm for surface patch analysis capable of quantifying the characteristics of hydrophobic patches. By calculating physically meaningful interaction energies, we can discern between the propensity for high and low viscosity due to the hydrophobic effect. Furthermore, by analyzing antibodies with problematic hydrophobic patches, we introduce a theory explaining their solubilization. This method is adaptable to any protein format and can be generalized for early in silico screening of viscosity in protein-based biopharmaceutical solutions.