On the application of structure-specific bulk-­solvent models

It is often discussed, mainly in connection with the rather high macromolecular R factors, that the treatment of bulk solvent in macromolecular refinement may lack the detail needed for modelling the solvent environment of molecules as complex as proteins and nucleic acids. This line of thought directly leads to the hypothesis that improvements in the modelling of the bulk solvent may substantially improve the agreement between the experimental data and the crystallographic models. Here, part of this hypothesis is being tested through the construction, via molecular-dynamics simulations, of a highly detailed, physics-based, structure-specific and crystallographic data-agnostic model of the bulk solvent of a known crystal structure. The water-distribution map obtained from the simulation is converted (after imposing space-group symmetry) to a constant (but scalable) partial structure factor which is then added in a re-refinement of the crystal structure. Compared with the simple Babinet-based correction, a reduction of the totally cross-validated free R value by 0.3% is observed. The implications and possible interpretations of these results are discussed.