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Cited by 310Computational Drug Discovery MethodsProtein Structure and DynamicsAdvanced Chemical Physics Studies

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Predicting Absolute Ligand Binding Free Energies to a Simple Model Site

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Mobley, David L., Graves, Alan P., Chodera, John D., McReynolds, Andrea C., Shoichet, Brian K., Dill, Ken A.·2007·Journal of Molecular Biology
DOI 10.1016/j.jmb.2007.06.002PMC PMC2104542
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Abstract

A central challenge in structure-based ligand design is the accurate prediction of binding free energies. Here we apply alchemical free energy calculations in explicit solvent to predict ligand binding in a model cavity in T4 lysozyme. Even in this simple site, there are challenges. We made systematic improvements, beginning with single poses from docking, then including multiple poses, additional protein conformational changes, and using an improved charge model. Computed absolute binding free energies had an RMS error of 1.9 kcal/mol relative to previously determined experimental values. In blind prospective tests, the methods correctly discriminated between several true ligands and decoys in a set of putative binders identified by docking. In these prospective tests, the RMS error in predicted binding free energies relative to those subsequently determined experimentally was only 0.6 kcal/mol. X-ray crystal structures of the new ligands bound in the cavity corresponded closely to predictions from the free energy calculations, but sometimes differed from those predicted by docking. Finally, we examined the impact of holding the protein rigid, as in docking, with a view to learning how approximations made in docking affect accuracy and how they may be improved.

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Research works printed but not linked: 52

  1. Shoichet, 1999, Ligand solvation in molecular docking, Proteins: Struct. Funct. Genet., 34, 4, 10.1002/(SICI)1097-0134(19990101)34:1<4::AID-PROT2>3.0.CO;2-6 · DOI
  2. Huang, 2006, Molecular mechanics methods for predicting protein–ligand binding, Phys. Chem. Chem. Phys., 8, 5166, 10.1039/B608269F · DOI
  3. Srinivasan, 1998, Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate-DNA helices, J. Am. Chem. Soc., 120, 9401, 10.1021/ja981844+ · DOI
  4. Kuhn, 2000, Binding of a diverse set of ligands to avidin and streptavidin: an accurate quantitative prediction of their relative affinities by a combination of molecular mechanics and continuum solvent models, J. Med. Chem., 43, 3786, 10.1021/jm000241h · DOI
  5. Allen, 2004, On the importance of atomic fluctuations, protein flexibility, and solvent in ion permeation, J. Gen. Physiol., 124, 679, 10.1085/jgp.200409111 · DOI
  6. Lee, 2006, Calculation of absolute protein–ligand binding affinity using path and endpoint approaches, Biophys. J., 90, 864, 10.1529/biophysj.105.071589 · DOI
  7. Pearlman, 2005, Evaluating the molecular mechanics Poisson–Boltzmann surface area free energy method using a congeneric series of ligands to p38 map kinase, J. Med. Chem., 48, 7796, 10.1021/jm050306m · DOI
  8. Steinbrecher, 2006, A multistep approach to structure-based drug design: studying ligand binding at the human neutrophil elastase, J. Med. Chem., 49, 1837, 10.1021/jm0505720 · DOI
  9. Woo, 2005, Calculation of absolute protein–ligand binding free energy from computer simulations, Proc. Natl Acad. Sci. USA, 102, 6825, 10.1073/pnas.0409005102 · DOI · Paper page
  10. Zhang, 2006, Potentials of mean force for acetylcholine unbinding from the alpha7 nicotinic acetylcholine receptor ligand-binding domain, J. Am. Chem. Soc., 128, 3019, 10.1021/ja057292u · DOI
  11. Rodinger, 2005, Enhancing the accuracy, the efficiency and the scope of free energy simulations, Curr. Opin. Struct. Biol., 15, 164, 10.1016/j.sbi.2005.03.001 · DOI
  12. Kofke, 2005, Free energy methods in molecular simulation, Fluid Phase Equilib., 228–229, 41, 10.1016/j.fluid.2004.09.017 · DOI
  13. Shirts, M. R., Mobley, D. L. & Chodera, J. D. Alchemical free energy calculations: ready for prime time? Ann. Rep. Comp. Chem. In the press. · DOI
  14. Roux, 1996, Thermodynamic stability of water molecules in the bacteriorhodopsin proton channel: a molecular dynamics free energy perturbation study, Biophys. J., 71, 670, 10.1016/S0006-3495(96)79267-6 · DOI
  15. Gilson, 1997, The statistical-thermodynamic basis for computation of binding affinities: a critical review, Biophys. J., 72, 1047, 10.1016/S0006-3495(97)78756-3 · DOI
  16. Hermans, 1997, Inclusion of the loss of translational and rotational freedom in theoretical estimates of free energies of binding. Application to a complex of benzene and mutant T4 lysozyme, J. Am. Chem. Soc., 119, 2707, 10.1021/ja963568+ · DOI
  17. Boresch, 2003, Absolute binding free energies: a quantitative approach for their calculation, J. Phys. Chem., B, 107, 9535, 10.1021/jp0217839 · DOI · Paper page
  18. Wang, 2006, Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials, Biophys. J., 91, 2798, 10.1529/biophysj.106.084301 · DOI
  19. Fujitani, 2005, Direct calculation of the binding free energies of FKBP ligands, J. Chem. Phys., 123, 084108, 10.1063/1.1999637 · DOI
  20. Deng, 2006, Calculation of standard binding free energies: aromatic molecules in the internal cavity of the T4 lysozyme L99A mutant, J. Chem. Theory Comput., 2, 1255, 10.1021/ct060037v · DOI
  21. van den Bosch, 2005, Calculation of the redox potential of the protein azurin and some mutants, Chem. Bio. Chem, 6, 738, 10.1002/cbic.200400244 · DOI
  22. Zhou, 2006, Computational study of ground-state chiral induction in small peptides: comparison of the relative stability of selected amino acid dimers and oligomers in homochiral and heterochiral combinations, J. Comp. Chem., 27, 857, 10.1002/jcc.20378 · DOI
  23. Eriksson, 1992, Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect, Science, 255, 178, 10.1126/science.1553543 · DOI
  24. Eriksson, 1993, Similar hydrophobic replacements of leu99 and phe153 within the core of t4 lysozyme have different structural and thermodynamic consequences, J. Mol. Biol., 229, 747, 10.1006/jmbi.1993.1077 · DOI
  25. Morton, 1995, Specificity of ligand binding in a buried non-polar cavity of T4 lysozyme: linkage of dynamics and structural plasticity, Biochemistry, 34, 8576, 10.1021/bi00027a007 · DOI
  26. Morton, 1995, Energetic origins of specificity of ligand binding in an interior nonpolar cavity of T4 lysozyme, Biochemistry, 34, 8564, 10.1021/bi00027a006 · DOI
  27. Wei, 2004, Testing a flexible-receptor docking algorithm in a model binding site, J. Mol. Biol., 337, 1161, 10.1016/j.jmb.2004.02.015 · DOI
  28. Graves, 2005, Decoys for docking, J. Med. Chem., 48, 3714, 10.1021/jm0491187 · DOI
  29. Mann, 2000, Modeling protein–small molecule interactions: structure and thermodynamics of noble gases binding in a cavity in mutant phage T4 lysozyme L99A, J. Mol. Biol., 302, 979, 10.1006/jmbi.2000.4064 · DOI
  30. Mobley, D. L., Chodera, J. D. & Dill, K. A. Confine and release: obtaining correct binding free energies in the presence of protein conformational change. J. Chem. Theory Comput. 2007, http://dx.doi.org/10.1021/ct700032n. · DOI
  31. Mobley, 2007, Comparison of charge models for fixed-charge force fields: small-molecule hydration free energies in explicit solvent, J. Phys. Chem., B., 111, 2242, 10.1021/jp0667442 · DOI
  32. Chambers, 1996, Model for aqueous solvation based on class iv atomic charges and first solvation-shell effects, J. Phys. Chem., A, 100, 16385, 10.1021/jp9610776 · DOI
  33. Turnbull, 2003, On the value of c: can low affinity systems be studied by isothermal titration calorimetry?, J. Am. Chem. Soc., 125, 14859, 10.1021/ja036166s · DOI
  34. Lindahl, 2001, GROMACS 3.0: a package for molecular simulation and trajectory analysis, J. Mol. Mod., 7, 306, 10.1007/s008940100045 · DOI
  35. van der Spoel, 2005, GROMACS: fast, flexible, and free, J. Comput. Chem., 26, 1701, 10.1002/jcc.20291 · DOI
  36. Sorin, 2005, Exploring the helix–coil transition via all-atom equilibrium ensemble simulations, Biophys. J., 88, 2472, 10.1529/biophysj.104.051938 · DOI
  37. Kollman, 1996, Advances and continuing challenges in achieving realistic and predictive simulations of the properties of organic and biological molecules, Acc. Chem. Res., 29, 461, 10.1021/ar9500675 · DOI
  38. Wang, 2004, Development and testing of a general AMBER force field, J. Comp. Chem., 25, 1157, 10.1002/jcc.20035 · DOI
  39. Wang, 2006, Automatic atom type and bond type perception in molecular mechanical calculations, J. Mol. Graph. Model., 26, 247, 10.1016/j.jmgm.2005.12.005 · DOI
  40. Li, 1998, New class IV charge model for extracting accurate partial charges from wave functions, J. Phys. Chem., A, 102, 1820, 10.1021/jp972682r · DOI
  41. Jakalian, 2002, Fast, efficient generation of high-quality atomic charges. am1-bcc model: Ii. Parameterization and validation, J. Comput. Chem., 23, 1623, 10.1002/jcc.10128 · DOI
  42. Jakalian, 2000, Fast, efficient generation of high-quality atomic charges. am1-bcc model: I. Method, J. Comput. Chem., 21, 132, 10.1002/(SICI)1096-987X(20000130)21:2<132::AID-JCC5>3.0.CO;2-P · DOI
  43. Bennett, 1976, Efficient estimation of free energy differences from Monte Carlo data, J. Comput. Phys., 22, 245, 10.1016/0021-9991(76)90078-4 · DOI
  44. Shirts, 2005, Comparison of efficiency and bias of free energies computed by exponential averaging, the Bennett Acceptance Ratio, and thermodynamic integration, J. Chem. Phys., 122, 144107-1, 10.1063/1.1873592 · DOI
  45. Berendsen, 1984, Molecular dynamics with coupling to an external bath, J. Chem. Phys., 81, 3584, 10.1063/1.448118 · DOI
  46. Shirts, M. R., Mobley, D. L., Chodera, J. D. & Pande, V. S. Accurate and efficient corrections for missing dispersion interactions in molecular simulations. J. Phys. Chem., B. Submitted. · DOI
  47. Kumar, 1992, The weighted histogram analysis method for free-energy calculations on biomolecules: I. The method, J. Comp. Chem., 13, 1011, 10.1002/jcc.540130812 · DOI · Paper page
  48. Plotnikov, 1997, A new ultrasensitive scanning calorimeter, Anal. Biochem., 250, 237, 10.1006/abio.1997.2236 · DOI
  49. Poteete, 1991, Second-site revertants of an inactive t4 lysozyme mutant restore activity by restructuring the active site cleft, Biochemistry, 30, 1425, 10.1021/bi00219a037 · DOI
  50. Otwinowski, 1997, Processing of X-ray diffraction data collected in oscillation mode, Methods Enzymol., 276, 307, 10.1016/S0076-6879(97)76066-X · DOI · Paper page
  51. Murshudov, 1997, Refinement of macromolecular structures by the maximum-likelihood method, Acta Crystallogr., D Biol. Crystallogr., 53, 240, 10.1107/S0907444996012255 · DOI
  52. Shirts, M. R. Calculating Precise and Accurate Free Energies in Biomolecular Simulations. Ph.D. Dissertation, Stanford University, 2004. ProQuest location: http://wwwlib.umi.com/dissertations/fullcit/3153076.

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Metadata

Authors
Mobley, D. L., Graves, A. P., Chodera, J. D., McReynolds, A. C., Shoichet, B. K., & Dill, K. A.
Affiliations
University of California, San Francisco (US)
Corresponding author
  • Shoichet, Brian K.
  • Dill, Ken A.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2007-08
Volume
371
Issue
4
Pages
1118-1134
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2007.06.002
PMC
PMC2104542
OpenAlex
W2128494768
Cited by
310
References
0
Citations by year
2026: 7 · 2025: 9 · 2024: 19 · 2023: 8 · 2022: 21 · 2021: 11 · 2020: 14 · 2019: 10 · 2018: 20 · 2017: 12 · 2016: 21 · 2015: 12 · 2014: 12 · 2013: 19 · 2012: 24
FWCI
23.38
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (GM63592)
  • U.S. Air Force
  • University of California, San Francisco
  • National Institute of General Medical Sciences (R01GM063592, R56GM063592, R01GM034993, GM59957, R01GM059957, GM63592)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Advanced Chemical Physics Studies
Keywords
absolute binding free energy, alchemical free energy calculations, T4 lysozyme, structure-based ligand design, explicit solvent, protein conformational change, charge model, docking, decoy discrimination, protein-ligand binding
MeSH terms
Binding Sites, Computer Simulation, Ligands, Models, Molecular, Protein Binding, Proteins, Temperature, Titrimetry, Protein Structure, Tertiary, Crystallography, X-Ray, Hydrophobic and Hydrophilic Interactions

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