Abstract
Water molecules in the binding site of a protein significantly influence protein structure and function, for example, by mediating protein–ligand interactions or due to water displacement as driving force for ligand binding. The knowledge about location and thermodynamic contributions of binding site water molecules is crucial for understanding protein function. WATsite is a hydration site analysis program that was developed together with an easy-to-use graphical user interface (GUI) based on PyMOL. WATsite identifies hydration sites from a molecular dynamics (MD) simulation trajectory with four different types of explicit water molecules. Hydration sites can be identified with or without the presence of a bound ligand dependent on the scientific problem. The protein desolvation free energy can be estimated for any ligand by summation of the hydration site free energies of the displaced hydration sites. The location and thermodynamic profile of hydration sites mediating the protein-ligand interactions is important for understanding protein-ligand binding. The WATsite program and GUI are available free of charge from http://people.pharmacy.purdue.edu/~mlill/software/watsite/version2.shtml.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Cheung MS, Garcia AE, Onuchic JN (2002) Protein folding mediated by solvation: water expulsion and formation of the hydrophobic core occur after the structural collapse. Proc Natl Acad Sci U S A 99(2):685–690
Gao M et al (2010) Water dynamics clue to key residues in protein folding. Biochem Biophys Res Commun 392(1):95–99
Kovacs IA, Szalay MS, Csermely P (2005) Water and molecular chaperones act as weak links of protein folding networks: energy landscape and punctuated equilibrium changes point towards a game theory of proteins. FEBS Lett 579(11):2254–2260
Sessions RB, Thomas GL, Parker MJ (2004) Water as a conformational editor in protein folding. J Mol Biol 343(4):1125–1133
Vajda T, Perczel A (2014) Role of water in protein folding, oligomerization, amyloidosis and miniprotein. J Pept Sci 20(10):747–759
Zuo G, Hu J, Fang H (2009) Effect of the ordered water on protein folding: an off-lattice Go-like model study. Phys Rev E Stat Nonlinear Soft Matter Phys 79(3 Pt 1):031925
Biela A et al (2012) Water makes the difference: rearrangement of water solvation layer triggers non-additivity of functional group contributions in protein-ligand binding. ChemMedChem 7(8):1423–1434
Breiten B et al (2013) Water networks contribute to enthalpy/entropy compensation in protein-ligand binding. J Am Chem Soc 135(41):15579–15584
Li Z, Lazaridis T (2006) Thermodynamics of buried water clusters at a protein-ligand binding interface. J Phys Chem B 110(3):1464–1475
Michel J, Tirado-Rives J, Jorgensen WL (2009) Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization. J Am Chem Soc 131(42):15403–15411
Baron R, Setny P, McCammon JA (2010) Water in cavity-ligand recognition. J Am Chem Soc 132(34):12091–12097
Bortolato A et al (2013) Water network perturbation in ligand binding: adenosine A(2A) antagonists as a case study. J Chem Inf Model 53(7):1700–1713
Hummer G (2010) Molecular binding: under Water’s influence. Nat Chem 2(11):906–907
Ladbury JE (1996) Just add water! The effect of water on the specificity of protein-ligand binding sites and its potential application to drug design. Chem Biol 3(12):973–980
Chen JM et al (1998) Structure-based design of potent inhibitors of scytalone dehydratase: displacement of a water molecule from the active site. Biochemistry 37(51):17735–17744
Gerogiokas G et al (2015) Evaluation of water displacement energetics in protein binding sites with grid cell theory. Phys Chem Chem Phys 17(13):8416–8426
Wissner A et al (2000) 4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors. J Med Chem 43(17):3244–3256
Pronk S et al (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29(7):845–854
Case DA et al (2014) AMBER 14. University of California, San Francisco
Word JM et al (1999) Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J Mol Biol 285(4):1735–1747
The PyMOL Molecular Graphics System, Version 1.8 Schrödinger, LLC
Hu B, Lill MA (2012) Protein pharmacophore selection using hydration-site analysis. J Chem Inf Model 52(4):1046–1060
Hu B, Lill MA (2014) Watsite: hydration site prediction program with pymol interface. J Comput Chem 35(16):1255–1260
Lindorff-Larsen K et al (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 78(8):1950–1958
Yang Y, Hu B, Lill MA (2014) Analysis of factors influencing hydration site prediction based on molecular dynamics simulations. J Chem Inf Model 54(10):2987–2995
Zielkiewicz J (2005) Structural properties of water: comparison of the SPC, SPCE, TIP4P, and TIP5P models of water. J Chem Phys 123(10):104501
Horn HW et al (2004) Development of an improved four-site water model for biomolecular simulations: TIP4P-Ew. J Chem Phys 120(20):9665–9678
Ester M et al (1996) A density-based algorithm for discovering clusters in large spatial databases with noise. In: Proceedings of the second international conference on knowledge discovery and data mining (KDD-96). AAAI Press, Menlo Park
Heyer LJ, Kruglyak S, Yooseph S (1999) Exploring expression data: identification and analysis of coexpressed genes. Genome Res 9(11):1106–1115
Acknowledgments
The authors gratefully acknowledge a grant from the NIH (GM092855) for partially supporting this research.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media LLC
About this protocol
Cite this protocol
Yang, Y., Hu, B., Lill, M.A. (2017). WATsite2.0 with PyMOL Plugin: Hydration Site Prediction and Visualization. In: Kihara, D. (eds) Protein Function Prediction. Methods in Molecular Biology, vol 1611. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7015-5_10
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7015-5_10
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-7013-1
Online ISBN: 978-1-4939-7015-5
eBook Packages: Springer Protocols