Multimodal chromatography uses multiple modes of interaction ranging from charge and hydrogen bonding interactions to hydrophobic and aromatic interactions to achieve challenging separations and unique selectivities. Unfortunately, these modes of interactions often affect each other in unintuitive ways making overall chromatographic behavior challenging to understand and predict. The lack of fundamental understanding of these systems poses a significant barrier to multimodal process development and multimodal ligand design.<br/><br/>In this work, we use molecular dynamics simulations to study a series of multimodal cation exchange and anion exchange ligands including commercially available ligands and a series of prototypical ligands. We first study these ligands in free solution and characterize each ligand’s conformational equilibria (which control the proximity of different chemical moieties) and hydration patterns (which control the overall hydrophobicity of the ligand). We find that conformational equilibria and hydration patterns are a strong function of the individual moieties comprising the ligand and their arrangement. We then simulate each ligand immobilized on a surface at typical commercially available ligand densities. We find that upon immobilizing ligands on a surface, they may associate (depending on conformational equilibria) to form patterned surfaces with large charge and hydrophobic patches on length scales exceeding the length scales of the individual ligands themselves. We characterize the hydration of these surfaces and find that surface hydrophobicity is a complex function of both individual ligand hydrophobicity and larger scale pattern formation. Finally, we simulate small model proteins interacting with selected ligand surfaces and demonstrate that these differences in hydration lead to differences in free energies of binding. Based on these results we define a set of rules for how individual ligand structure and arrangement controls the hydrophobic and charge characteristics of the chromatographic surface. This work provides an important step toward understanding the relationship between ligand design and function in a chromatographic system. In the future, we plan to investigate the relationship between the hydrophobic and charge characteristics of the chromatographic surface and orthogonality in experimental chromatographic systems.

Effect of ligand structure, arrangement, and density on charge and hydrophobic characteristics of multimodal chromatographic surface

2019 Spring National Meeting

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