Enhancing Structure Prediction and Design of Soluble and Membrane Proteins with Explicit Solvent-Protein Interactions

Solvent molecules interact intimately with proteins and can profoundly regulate their structure and function. However, accurately and efficiently modeling protein solvation effects at the molecular level has been challenging. Here, we present a method that improves the atomic-level modeling of soluble and membrane protein structures and binding by efficiently predicting de novo protein-solvent molecule interactions. The method predicted with unprecedented accuracy buried water molecule positions, solvated protein conformations, and challenging mutational effects on protein binding. When applied to homology modeling, solvent-bound membrane protein structures, pockets, and cavities were recapitulated with near-atomic precision even from distant homologs. Blindly refined atomic-level structures of evolutionary distant G protein-coupled receptors imply strikingly different functional roles of buried solvent between receptor classes. The method should prove useful for refining low-resolution protein structures, accurately modeling drug-binding sites in structurally uncharacterized receptors, and designing solvent-mediated protein catalysis, recognition, ligand binding, and membrane protein signaling.