Although, there is 20–30% dehydration of the overall ligand upon binding, the hydrogen-bonding sites are dehydrated to a much smaller extent, particularly in cis-like configurations. MD simulations of ligands in free solution with three therapeutic antibody fragments show that ligand conformational equilibria remain effectively unchanged upon binding to proteins. Interestingly, in ethanol and water, hydrogen bonding among the amide hydrogen and solvent molecules stabilizes two additional conformations of Capto MMC in which ω takes on more » less favorable cis-like configurations. This has the overall result of “flattening out” the conformational landscape. In an LJ liquid, solvent molecules compete with intramolecular interactions while simultaneously providing an osmotic force, stabilizing both closer and farther distances between ligand sites. In a high dielectric medium, Capto MMC preferentially samples three conformations, which are stabilized by a combination of an intramolecular torsion potential (on ω) and LJ interactions. By mapping ligand conformations onto two key torsion angles, ω and φ, in these solvents and in low and high dielectric media, we quantify the relative importance of intramolecular and solvent-mediated interactions. In this report, we determine conformational equilibria of two commercially used multimodal cation exchange ligands, Capto MMC and Nuvia cPrime, in a range of solvents, a Lennard-Jones (LJ) liquid, ethanol, and water, using molecular dynamics (MD) simulations. The mechanism by which multimodal ligands interact with proteins is expected to be affected by ligand conformations, among other factors. Multimodal chromatography uses small ligands with multiple modes of interaction, e.g., charged, hydrophobic or hydrogen bonding, to separate proteins from complex mixtures.
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