Schematic illustration of protein–surface interactions in aqueous solvent. The main interaction interfaces can be categorized as: protein–surface, protein–solvent, solvent–surface and protein–solvent–surface. The protein-surface interface (depicted in the left circle) includes direct interactions. The interactions can be non-specific such as van der Waals and electrostatic interactions (represented with dashed lines in the figure), or specific such as strong histidine–gold interactions (shown with a continuous line) and even stronger chemisorption interactions. At the protein-solvent interface (depicted in the top circle), the structural and physical properties of the protein and the solvent deviate from those inside the protein and in the bulk solvent, respectively. In particular, water forms layers around the polar and charged residues as depicted by the two spheres in the figure. At the interface, the relative dielectric permittivity of water and of the protein is lower than that of their bulk counterparts. At the solvent-surface interface (depicted in the right circle), the solvent may form structured layers or be completely disordered. On a gold surface, for instance, water forms two ordered layers that are separated by high energy barriers and have a lowered relative dielectric permittivity in the direction normal to the surface. At the protein-solvent-surface interface (depicted in the bottom circle), the interactions involve a complex interplay between the constituents. The protein may make strong indirect interactions with the surface through a stable network of hydrogen bonds (represented by dashed lines) in the adsorption region.