+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Strategies to calculate water binding free energies in protein-ligand complexes

Strategies to calculate water binding free energies in protein-ligand complexes

Journal of Chemical Information and Modeling 54(6): 1623-1633

Water molecules are commonplace in protein binding pockets, where they can typically form a complex between the protein and a ligand or become displaced upon ligand binding. As a result, it is often of great interest to establish both the binding free energy and location of such molecules. Several approaches to predicting the location and affinity of water molecules to proteins have been proposed and utilized in the literature, although it is often unclear which method should be used under what circumstances. We report here a comparison between three such methodologies, Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC), and double-decoupling, in the hope of understanding the advantages and limitations of each method when applied to enclosed binding sites. As a result, we have adapted the JAWS scoring procedure, allowing the binding free energies of strongly bound water molecules to be calculated to a high degree of accuracy, requiring significantly less computational effort than more rigorous approaches. The combination of JAWS and GCMC offers a route to a rapid scheme capable of both locating and scoring water molecules for rational drug design.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 055934256

Download citation: RISBibTeXText

PMID: 24684745

DOI: 10.1021/ci400674k

Related references

Applying physics-based scoring to calculate free energies of binding for single amino acid mutations in protein-protein complexes. Plos one 8(12): E82849, 2013

Combined quantum mechanics/molecular mechanics (QM/MM) simulations for protein-ligand complexes: free energies of binding of water molecules in influenza neuraminidase. Journal of Physical Chemistry. B 119(3): 997, 2015

Structure and thermodynamics of RNA-protein binding: using molecular dynamics and free energy analyses to calculate the free energies of binding and conformational change. Journal of Molecular Biology 297(5): 1145-1158, 2000

Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water. Faraday Discussions 169: 477-499, 2014

A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies. Journal of Chemical Physics 134(5): 054114, 2011

Computational study of ligand binding in lipid transfer proteins: Structures, interfaces, and free energies of protein-lipid complexes. Journal of Computational Chemistry 33(22): 1831-1844, 2012

Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. Journal of Medicinal Chemistry 47(18): 4507-4516, 2004

Nonpolar Solvation Free Energies of Protein-Ligand Complexes. Journal of Chemical Theory and Computation 6(11): 3558-3568, 2010

Comparison of the Efficiency of the LIE and MM/GBSA Methods to Calculate Ligand-Binding Energies. Journal of Chemical Theory and Computation 7(11): 3768-3778, 2011

Protein-ligand binding free energies from exhaustive docking. Journal of Physical Chemistry. B 116(23): 6872-6879, 2012

Theoretical study of the ligand-CYP2B4 complexes: effect of structure on binding free energies and heme spin state. Proteins 55(4): 895-914, 2004

Protein:Ligand binding free energies: A stringent test for computational protein design. Journal of Computational Chemistry 37(4): 404-415, 2016

Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water. Journal of Medicinal Chemistry 45(12): 2469-2483, 2002

Application of RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvation. Journal of the American Chemical Society 115(21): 9620-9631, 1993

Protein-Ligand Electrostatic Binding Free Energies from Explicit and Implicit Solvation. Journal of Chemical Theory and Computation 11(9): 4450-4459, 2015