Unwanted protein aggregation is a critical concern in biopharmaceutical development, adversely affecting activity, delivery, and biotherapeutic solution stability. To combat aggregation, formulations are typically derived that involve addition of salts, sugars, and zwitterionic excipients, though in many cases the specific effects and specific modulations of protein-protein interactions due to these additives are poorly understood. In order to help address these concerns, we performed a series of molecular mechanics investigations to explore the dynamics of zwitterionic excipients and how their addition to protein solutions alter individual protein conformer ensembles and direct protein-protein association. We observe quantitative agreement between simulations and nuclear magnetic resonance in zwitterionic solute dynamics studies. In simulations in the presence of protein structures, we identify how excipients partition near protein features and detail how they specifically work to mediate interactions in solution. This study gives a detailed view of the dynamics and partitioning of excipients and we believe provides valuable molecular level insight into complex biomolecular solutions.

Modeling of zwitterionic molecule dynamics and their role in protein stabilization

2019 Fall National Meeting

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