Efficient consideration of coordinated water molecules improves computational protein-protein and protein-ligand docking discrimination
Open Access
- 21 September 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Computational Biology
- Vol. 16 (9), e1008103
- https://doi.org/10.1371/journal.pcbi.1008103
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. 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 this paper, we describe a method to efficiently consider these water molecules both implicitly and explicitly at the interfaces formed by two polar molecules. 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.Keywords
Funding Information
- Center for Scientific Review (GM123089)
- National Institutes of Health (GM123089)
This publication has 36 references indexed in Scilit:
- Are Protein Force Fields Getting Better? A Systematic Benchmark on 524 Diverse NMR MeasurementsJournal of Chemical Theory and Computation, 2012
- Extensive protein and DNA backbone sampling improves structure-based specificity prediction for C2H2 zinc fingersNucleic Acids Research, 2011
- Rosetta3Methods in Enzymology, 2010
- Protein–protein docking benchmark version 4.0Proteins, 2010
- Three-Dimensional Molecular Theory of Solvation Coupled with Molecular Dynamics in AmberJournal of Chemical Theory and Computation, 2010
- Binding MOAD, a high-quality protein ligand databaseNucleic Acids Research, 2007
- Predicting Absolute Ligand Binding Free Energies to a Simple Model SiteJournal of Molecular Biology, 2007
- Motifs for molecular recognition exploiting hydrophobic enclosure in protein–ligand bindingProceedings of the National Academy of Sciences of the United States of America, 2007
- ROSETTALIGAND: Protein–small molecule docking with full side‐chain flexibilityProteins-Structure Function and Bioinformatics, 2006
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004