Multimodal chromatography uses multiple modes of interaction ranging from charge and aromatic to hydrophobic and hydrogen bonding to achieve challenging separations and unique selectivities. These modes of interactions affect each other in non-intuitive ways making overall chromatographic behavior difficult to understand and predict. The lack of fundamental understanding of these systems poses a significant barrier to multimodal process development and multimodal ligand design. In this work, we employ molecular modeling and simulations to obtain fundamental understanding of how multimodal ligands interact with proteins. Specifically, we examine interactions between a set of multimodal cation exchange ligands and a set of chemically diverse antibody fragments. First, we focused on how ligand chemistry and architecture affect hydration and dynamics using molecular dynamics simulations of ligands in aqueous solution. Second, we investigated ligand-protein binding phenomena using molecular simulations of proteins in aqueous solutions of free ligands. We also performed simulations of ligands immobilized on a SAM surface to study the effect of immobilization and ligand density on ligand solvation and conformation. Finally, specific faces of the protein surface were chosen based on the free ligand simulations results and umbrella sampling simulations were performed to obtain free energies of binding of these faces to multimodal ligands immobilized on a SAM surface. Collectively, our work provides a deeper understanding for how protein and multimodal ligand attributes result in different chromatographic selectivities. This will serve to guide design of new multimodal ligands as well as resin selection for multimodal polishing steps.

Effects of protein and ligand structure on protein-multimodal ligand interactions in antibody systems

255th National Meeting (2018)

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