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Predicting absolute ligand binding free energies to a simple model site.

Mobley DL, Graves AP, Chodera JD, McReynolds AC, Shoichet BK, Dill KA
J Mol Biol 371 1118-34 (2007)
Related entries: 2oty, 2otz

Cited: 160 times
EuropePMC logo PMID: 17599350

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.

Articles - 2ou0 mentioned but not cited (3)

  1. Predicting absolute ligand binding free energies to a simple model site. Mobley DL, Graves AP, Chodera JD, McReynolds AC, Shoichet BK, Dill KA. J Mol Biol 371 1118-1134 (2007)
  2. Small-molecule ligand docking into comparative models with Rosetta. Combs SA, Deluca SL, Deluca SH, Lemmon GH, Nannemann DP, Nguyen ED, Willis JR, Sheehan JH, Meiler J. Nat Protoc 8 1277-1298 (2013)
  3. Identifying ligand binding sites and poses using GPU-accelerated Hamiltonian replica exchange molecular dynamics. Wang K, Chodera JD, Yang Y, Shirts MR. J Comput Aided Mol Des 27 989-1007 (2013)


Reviews citing this publication (19)

  1. Binding of small-molecule ligands to proteins: "what you see" is not always "what you get". Mobley DL, Dill KA. Structure 17 489-498 (2009)
  2. Alchemical free energy methods for drug discovery: progress and challenges. Chodera JD, Mobley DL, Shirts MR, Dixon RW, Branson K, Pande VS. Curr Opin Struct Biol 21 150-160 (2011)
  3. Computations of standard binding free energies with molecular dynamics simulations. Deng Y, Roux B. J Phys Chem B 113 2234-2246 (2009)
  4. Entropy-enthalpy compensation: role and ramifications in biomolecular ligand recognition and design. Chodera JD, Mobley DL. Annu Rev Biophys 42 121-142 (2013)
  5. Predicting Binding Free Energies: Frontiers and Benchmarks. Mobley DL, Gilson MK. Annu Rev Biophys 46 531-558 (2017)
  6. Prediction of protein-ligand binding affinity by free energy simulations: assumptions, pitfalls and expectations. Michel J, Essex JW. J Comput Aided Mol Des 24 639-658 (2010)
  7. Docking Screens for Novel Ligands Conferring New Biology. Irwin JJ, Shoichet BK. J Med Chem 59 4103-4120 (2016)
  8. Molecular recognition and ligand association. Baron R, McCammon JA. Annu Rev Phys Chem 64 151-175 (2013)
  9. Classical electrostatics for biomolecular simulations. Cisneros GA, Karttunen M, Ren P, Sagui C. Chem Rev 114 779-814 (2014)
  10. Structure-based systems biology for analyzing off-target binding. Xie L, Xie L, Bourne PE. Curr Opin Struct Biol 21 189-199 (2011)
  11. Statistical mechanics and molecular dynamics in evaluating thermodynamic properties of biomolecular recognition. Wereszczynski J, McCammon JA. Q Rev Biophys 45 1-25 (2012)
  12. Advances in free-energy-based simulations of protein folding and ligand binding. Perez A, Morrone JA, Simmerling C, Dill KA. Curr Opin Struct Biol 36 25-31 (2016)
  13. Recent theoretical and computational advances for modeling protein-ligand binding affinities. Gallicchio E, Levy RM. Adv Protein Chem Struct Biol 85 27-80 (2011)
  14. A survey of the year 2007 literature on applications of isothermal titration calorimetry. Bjelić S, Jelesarov I. J Mol Recognit 21 289-312 (2008)
  15. Protein storytelling through physics. Brini E, Simmerling C, Dill K. Science 370 eaaz3041 (2020)
  16. Recent Developments in Free Energy Calculations for Drug Discovery. King E, Aitchison E, Li H, Luo R. Front Mol Biosci 8 712085 (2021)
  17. Toward a molecular understanding of the interaction of dual specificity phosphatases with substrates: insights from structure-based modeling and high throughput screening. Bakan A, Lazo JS, Wipf P, Brummond KM, Bahar I. Curr Med Chem 15 2536-2544 (2008)
  18. Structure-based in silico approaches for drug discovery against Mycobacterium tuberculosis. Kingdon ADH, Alderwick LJ. Comput Struct Biotechnol J 19 3708-3719 (2021)
  19. The slow but steady rise of binding free energy calculations in drug discovery. Xu H. J Comput Aided Mol Des 37 67-74 (2023)

Articles citing this publication (138)



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