Mixed-mode ligands tend to exhibit unique selectivity for certain proteins as compared to other mixed-mode, hydrophobic or ion-exchange ligands.  However, the molecular-level mechanism underlying this selectivity is not well understood, resulting in a large design space to screen for each target product.  In this study, we set out to define the relationship between structural characteristics of the ligand (e.g. geometric organization/separation of modalities, secondary interactions, oxidized groups) and selectivity against a diverse library of proteins.  This was accomplished by generating homologous libraries of two commercial mixed-mode cation-exchange ligands through targeted chemical modifications and measuring protein retention in a salt-based linear gradient elution step.  These screening results were used to determine ligand characteristics which contribute to protein selectivity and can be used to select a concise set of ligands that encompass the majority of protein selection mechanisms available in multimodal systems.

Probing protein-ligand selectivity in multimodal chromatography systems through the use of homologous mixed-mode ligand libraries

247th National Meeting (2014)

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