The molecular interaction process

Abstract Noncovalent molecular interactions, which are central to life, are thermodynamic processes that follow common interaction pathways. This commentary provides a foundation both for considering non-covalent interactions and the interplay between the protein properties and the solvent properties in determining the energetics. In biopharmaceutics non-covalent interactions are a two-edged sword. Foremost, they provide a core function for biopharmaceutical agents, binding to targets, substrates or receptors. At the same time, they are at the root of the solubility and viscosity difficulties encountered in the manufacture, formulation and delivery of protein-based pharmaceuticals. This commentary describes the interaction process and summarizes the energetics of the interaction pathway. The focus will be on protein-protein interactions, while recognizing that the processes and energetics are entirely general and applicable to all solution interactions. The contributions of protein molecular properties and protein colloidal properties to the pathway are described, and the relationship between the two is developed. The processes leading to protein-protein binding are described with respect to the attractive interactions that lead to aggregation and high viscosity. The concept of emergent heterogeneity is introduced, and a model presented for how non-contacting interactions may lead to high viscosities without simultaneously causing low solubility.