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 ordered water molecules on the surfaces of proteins. A two-stage method 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 discrimination tests.
Highlights
Water plays a significant role in biomolecular structure
Well-coordinated water molecules—those forming multiple hydrogen bonds with nearby polar groups—play an important role in the structure of biomolecular systems, yet the effect of these waters is often not considered in molecular energy computations
In computations related to determining how a protein interacts with binding partners, we show that the use of this new method significantly improves results. Future application of this approach may improve the design of new protein and small molecule drugs
Summary
Water plays a significant role in biomolecular structure. The hydrophobic effect drives the collapse of proteins into their general shape while highly coordinated water molecules (water molecules making multiple water-protein hydrogen bonds) on the surface of a protein may confer specific conformations to nearby polar groups. Water plays a key role in biomolecular recognition: when a ligand binds its host in an aqueous environment, it must displace water molecules on the surface and energetically compensate for the lost interactions [1]. Explicit solvent calculations are computationally expensive, in Monte Carlo simulations where a long water equilibration period might be required. Such a cost may be alleviated through the use of an implicit solvent[4] model, which while more efficient, incurs a loss of accuracy by disregarding the energetics of highly-coordinated water molecules[5]. Several such methods have been developed but tend to be developed for specific types of interactions (eg. protein-protein or protein-small molecule ligand) [6,7,8,9,10,11] or are computationally expensive[12]
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