Multimodal chromatography has emerged as an extremely promising form of chromatography. Recent studies have shown that enhanced selectivities can be achieved in multimodal systems by the appropriate choice of ligand chemistry and fluid phase modifiers. However, the mechanistic details essential to optimize desired bioseparations are still missing in these systems. The work presented here employs all-atom explicit solvent molecular dynamics (MD) simulations to obtain fundamental, molecular understanding of the nature of interactions between proteins and different multimodal ligands. While it is expected that these interactions involve a combination of multiple constituent modes present on the ligands, differences in structural arrangement of these chemical moieties result in significantly different �synergism� in protein-ligand interactions. The relative importance of the individual modes of interactions also varies between different protein-ligand systems and the complex interplay of these interactions can result in unique selectivities as observed in chromatographic studies. These simulations, combined with experimental techniques including Nuclear Magnetic Resonance (NMR) and Isothermal Titration Calorimetry (ITC), have been used to study the underlying thermodynamics of these interactions and the importance of synergy and avidity in protein binding to a ligand surface. The role of water and how it mediates these multiple weak interactions resulting in regionally-selective pseudo-affinity interactions was also analyzed. Based on the insights gained from these simulations and protein surface characterization techniques, a faster, coarse-grained method was developed to predict protein retention behavior in multimodal chromatographic systems.

Elucidating the nature of multimodal ligand-protein interactions in chromatography: Insights into synergy and selectivity

247th National Meeting (2014)

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