ABSTRACT
Highly-coordinated water molecules are frequently an integral part of protein-protein and protein-ligand interfaces. We introduce an updated energy model that efficiently captures the energetic effects of these highly-coordinated water molecules on the surfaces of proteins. A two-stage protocol is developed in which polar groups arranged in geometries suitable for water placement are first identified, then a modified Monte Carlo simulation allows highly coordinated waters to be placed on the surface of a protein while simultaneously sampling amino acid side chain orientations. This “semi-explicit” water model is implemented in Rosetta and is suitable for both structure prediction and protein design. We show that our new approach and energy - model yield significant improvements in native structure recovery of protein-protein and protein-ligand docking.
Footnotes
Figure 1 expanded to show potentials of implicit water score. Benchmarking performed against 3D-RISM as implemented in AmberTools (results briefly mentioned in main text, with detailed results in Supplement) Additional clarifying statements made throughout.
ABBREVIATIONS
- Rosetta-ICO
- implicit consideration of coordinated water
- Rosetta-ECO
- explicit consideration of coordinated water
- PPI
- protein-protein interface
- RMSD
- root-mean-square deviation