Many biophysical and colloidal phenomena are driven by water-mediated interactions. The peculiar organization of water molecules – their packing and orientations – near solutes is governed by the balance between water-water and water-solute interactions, which in turn governs the strength of water-mediated interactions.  Here we employ molecular modeling and simulations to study the hydration and conformational preferences of a set of ligands commonly used in protein chromatography.  These ligands are conformationally flexible and comprise several similar chemical moieties (aromatic and aliphatic groups, amide groups, and carboxylates) but arranged in different chemical architectures.  We identify key hydration water molecules as well as hydrogen-bonded chains and clusters comprising 2, 3, and larger number of water molecules which play an important role in locking the ligands in specific conformations in aqueous solutions, as distinct from conformational basins in the gas phase.  We expect that these water networks will significantly impact the thermodynamics of water release upon protein-ligand binding.  We also studied how immobilization of the ligands to self-assembled monolayer (SAM) surfaces, and specifically ligand-ligand interactions on the surface (which depend on ligand architecture), affect their hydration and conformational preferences compared to that in free solution.  Our results illustrate the importance of both ligand chemistry and architecture in determining their conformation, hydration, and binding behavior for both free ligand systems and surface-immobilized systems.

Water-multimodal ligand interactions: The effect of ligand chemistry and architecture on ligand hydration and conformation in solution and at interfaces

255th National Meeting (2018)

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