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Free enthalpies of replacing water molecules in protein binding pockets

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Abstract

Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate the displacement of water molecules by an apolar probe in the binding pocket of two proteins, cyclin-dependent kinase 2 and tRNA-guanine transglycosylase, using the method of enveloping distribution sampling (EDS) to obtain free enthalpy differences. In both cases, a ligand core is placed inside the respective pocket and the remaining water molecules are converted to apolar probes, both individually and in pairs. The free enthalpy difference between a water molecule and a CH3 group at the same location in the pocket in comparison to their presence in bulk solution calculated from EDS molecular dynamics simulations corresponds to the binding free enthalpy of CH3 at this location. From the free enthalpy difference and the enthalpy difference, the entropic contribution of the displacement can be obtained too. The overlay of the resulting occupancy volumes of the water molecules with crystal structures of analogous ligands shows qualitative correlation between experimentally measured inhibition constants and the calculated free enthalpy differences. Thus, such an EDS analysis of the water molecules in the binding pocket may give valuable insight for potency optimization in drug design.

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References

  1. IUPAP (1978) Symbols, units and nomenclature in physics. Phys A 93A:1

    Google Scholar 

  2. IUPAC (1988) Quantities, units and symbols in physical chemistry. Blackwell Scientific Publications, Oxford

  3. Kirkwood JG (1935) Statistical mechanics of fluid mixtures. J Chem Phys 3:300–313

    Article  CAS  Google Scholar 

  4. Christ CD, van Gunsteren WF (2008) Multiple free energies from a single simulation: extending enveloping distribution sampling to non-overlapping phase-space distributions. J Chem Phys 128:174112

    Article  Google Scholar 

  5. Christ CD, van Gunsteren WF (2009) Simple, efficient, and reliable computation of multiple free energy differences from a single simulation: a reference Hamiltonian parameter update scheme for enveloping distribution sampling (EDS). J Chem Theory Comput 5:276–286

    Article  CAS  Google Scholar 

  6. Christ CD, van Gunsteren WF (2009) Comparison of three enveloping distribution sampling Hamiltonians for the estimation of multiple free energy differences from a single simulation. J Comput Chem 31:1664–1679

    Article  Google Scholar 

  7. Riniker S, Christ CD, Hansen N, Mark AE, Nair PC, van Gunsteren WF (2011) Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors. J Chem Phys 135:024105

    Article  Google Scholar 

  8. Gilson MK, Given JA, Bush BL, McCammon JA (1997) The statistical-thermodynamic basis for computation of binding affinities: a critical review. Biophys J 72:1047–1069

    Article  CAS  Google Scholar 

  9. Gilson MK, Zhou H-X (2007) Calculation of protein-ligand binding affinities. Annu Rev Biophys Biomol Struct 36:21–42

    Article  CAS  Google Scholar 

  10. Poornima CS, Dean PM (1995) Hydration in drug design. 1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions. J Comput Aided Mol Des 9:500–512

    Article  CAS  Google Scholar 

  11. Poornima CS, Dean PM (1995) Hydration in drug design. 2. Influence of local site surface shape on water binding. J Comput Aided Mol Des 9:513–520

    Article  CAS  Google Scholar 

  12. Poornima CS, Dean PM (1995) Hydration in drug design. 3. Conserved water molecules at the ligand-binding sites of homologous proteins. J Comput Aided Mol Des 9:521–531

    Article  CAS  Google Scholar 

  13. Minke WE, Dillers DJ, Hol WGJ, Verlinde CLMJ (1999) The role of waters in docking strategies with incremental flexibility for carbohydrate derivatives: heat-labile enterotoxin, a multivalent test case. J Med Chem 42:1778–1788

    Article  CAS  Google Scholar 

  14. Mancera RL (2002) De novo ligand design with explicit water molecules: an application to bacterial neuraminidase. J Comput Aided Mol Des 16:479–499

    Article  CAS  Google Scholar 

  15. de Graaf C, Pospisil P, Pos W, Folkers G, Vermeulen NPE (2005) Binding mode prediction of cytochrome P450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking. J Med Chem 48:2308–2318

    Article  Google Scholar 

  16. Verdonk ML, Chessari G, Cole JC, Hartshorn MJ, Murray CW, Nissink JWM, Taylor RD, Taylor R (2005) Modeling water molecules in protein-ligand docking using GOLD. J Med Chem 48:6504–6515

    Article  CAS  Google Scholar 

  17. Barillari C, Taylor J, Viner R, Essex JW (2007) Classification of water molecules in protein binding sites. J Am Chem Soc 129:2577–2587

    Article  CAS  Google Scholar 

  18. Abel R, Young T, Farid R, Berne BJ, Friesner RA (2008) Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J Am Chem Soc 130:2817–2831

    Article  CAS  Google Scholar 

  19. 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 131:15403–15411

    Article  CAS  Google Scholar 

  20. Beuming T, Farid R, Sherman W (2009) High-energy water sites determine peptide binding affinity and specificity of PDZ domains. Protein Sci 18:1609–1619

    Article  CAS  Google Scholar 

  21. Robinson DD, Sherman W, Farid R (2010) Understanding kinase selectivity through energetic analysis of binding site waters. Chem Med Chem 5:618–627

    CAS  Google Scholar 

  22. Pearlstein RA, Hu Q-Y, Zhou J, Yowe D, Levell J, Dale B, Kaushik VK, Daniels D, Hanrahan S, Sherman W, Abel R (2010) New hypotheses about the structure-function of proprotein convertase subtilisin/kexin type 9: analysis of the epidermal growth factor-like repeat A docking site using WaterMap. Proteins 78:2571–2586

    CAS  Google Scholar 

  23. Wang L, Berne BJ, Friesner RA (2011) Ligand binding to protein-binding pockets with wet and dry regions. Proc Natl Acad Sci USA 108:1326–1330

    Article  CAS  Google Scholar 

  24. Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R (1998) Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Mol Cell 1:553–563

    Article  CAS  Google Scholar 

  25. Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, Garman EF, Gibson AE, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Lawrie AM, Newell DR, Noble MEM, Sausville EA, Schultz R, Yu W (2000) Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 43:2798–2804

    Article  Google Scholar 

  26. Bramson HN, Corona J, Davis ST, Dickerson SH, Edelstein M, Frye SV, Gampe RT Jr, Harris PA, Hassell A, Holmes WD, Hunter RN, Lackey KE, Lovejoy B, Luzzio MJ, Montana V, Rocque WJ, Rusnak D, Shewchuk L, Veal JM, Walker DH, Kuyper LF (2001) Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis. J Med Chem 44:4339–4358

    Article  CAS  Google Scholar 

  27. Gibson AE, Arris CE, Bentley J, Boyle FT, Curtin NJ, Davies TG, Endicott JA, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Mesguiche V, Newell DR, Noble MEM, Tucker JA, Whitfield HJ (2002) Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O 6-substituted guanine derivatives. J Med Chem 45:3381–3393

    Article  CAS  Google Scholar 

  28. Chu X-J, DePinto W, Bartkovitz D, So S-S, Vu BT, Packman K, Lukacs C, Ding Q, Jiang N, Wang K, Goelzer P, Yin X, Smith MA, Higgins BX, Chen Y, Xiang Q, Moliterni J, Kaplan G, Graves B, Lovey A, Fotouhi N (2006) Discovery of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6-methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity. J Med Chem 49:6549–6560

    Article  CAS  Google Scholar 

  29. McIntyre NA, McInnes C, Griffiths G, Barnett AL, Kontopidis G, Slawin AMZ, Jackson W, Thomas M, Zheleva DI, Wang S, Blake DG, Westwood NJ, Fischer PM (2010) Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo-[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors. J Med Chem 53:2136–2145

    Article  CAS  Google Scholar 

  30. Okada N, Sasakawa C, Tobe T, Yamada M, Nagai S, Talukder KA, Komatsu K, Kanegasaki S, Yoshikawa M (1991) Virulence-associated chromosomal loci of Shigella flexneri identified by random Tn5 insertion mutagenesis. Mol Microbiol 5:187–195

    Article  CAS  Google Scholar 

  31. Kohler PC, Ritschel T, Schweizer WB, Klebe G, Diederich F (2009) High-affinity inhibitors of tRNA-guanine transglycosylase replacing the function of a structural water cluster. Chem Eur J 15:10809–10817

    Article  CAS  Google Scholar 

  32. Ritschel T, Kohler PC, Neudert G, Heine A, Diederich F, Klebe G (2009) How to replace the residual solvation shell of polar active site residues to achieve nanomolar inhibition of tRNA-guanine transglycosylase. ChemMedChem 4:2012–2023

    Article  CAS  Google Scholar 

  33. Schmid N, Christ CD, Christen M, Eichenberger AP, van Gunsteren WF (2012) Architecture, implementation and parallelization of the GROMOS software for biomolecular simulation. Comp Phys Comm 183:890–903

    Article  CAS  Google Scholar 

  34. Riniker S, Christ CD, Hansen HS, Hünenberger PH, Oostenbrink C, Steiner D, van Gunsteren WF (2011) Calculation of relative free energies for ligand-protein binding, solvation and conformational transitions using the GROMOS software. J Phys Chem B 115:13570–13577

    Article  CAS  Google Scholar 

  35. The GROMOS package of programs can be obtained from http://www.gromos.net

  36. Oostenbrink C, Villa A, Mark AE, van Gunsteren WF (2004) A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6. J Comput Chem 25:1656–1676

    Article  CAS  Google Scholar 

  37. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) In: Pullmann B (eds) Intermolecular forces. Reidel, Dordrecht, pp 331–342

  38. Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  39. Hockney RW (1970) The potential calculation and some applications. Methods Comput Phys 9:136–210

    Google Scholar 

  40. Tironi I, Sperb R, Smith PE, van Gunsteren WF (1995) A generalized reaction field method for molecular dynamics simulations. J Chem Phys 102:5451–5459

    Article  CAS  Google Scholar 

  41. Glättli A, Daura X, van Gunsteren WF (2002) Derivation of an improved SPC model for liquid water: SPC/A and SPC/L. J Chem Phys 116:9811–9828

    Article  Google Scholar 

  42. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341

    Article  CAS  Google Scholar 

  43. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242

    Article  CAS  Google Scholar 

  44. Fiser A, Sali A (2003) ModLoop: automated modeling of loops in protein structures. Bioinformatics 12:2500–2501

    Article  Google Scholar 

  45. Malde AK, Zuo L, Breeze M, Stroet M, Poger D, Nair PC, Oostenbrink C, Mark AE (2011) An automated force field topology builder (ATB) and repository: Version 1.0. J Chem Theory Comput 7:4026–4037

    Article  CAS  Google Scholar 

  46. Eichenberger AP, Allison JR, Dolenc J, Geerke DP, Horta BAC, Meier K, Oostenbrink C, Schmid N, Steiner D, Wang D, van Gunsteren WF (2011) The GROMOS++ software for the analysis of biomolecular simulation trajectories. J Chem Theory Comput 7:3379–3390

    Article  CAS  Google Scholar 

  47. Chodera JD, Swope WC, Pitera JW, Seok C, Dill KA (2007) Use of the weighted histogram analysis method for the analysis of simulated and parallel tempering simulations. J Chem Theory Comput 3:26–41

    Article  CAS  Google Scholar 

  48. Humphrey W, Dalke A, Schulten K (1996) VMD—visual molecular dynamics. J Mol Graph 14:33–38

    Article  CAS  Google Scholar 

  49. Christen M, Hünenberger PH, Bakowies D, Bürgi R, Geerke DP, Heinz TN, Kastenholz MA, Kräutler V, Oostenbrink C, Peter C, Trzesniak D, van Gunsteren WF (2005) The GRMOS software for biomolecular simulation: GROMOS05. J Comput Chem 26:1719–1751

    Article  CAS  Google Scholar 

  50. Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K i ) and the concentration of inhibitor which causes 50 % inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108

    Article  CAS  Google Scholar 

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Acknowledgments

This work was financially supported by the National Center of Competence in Research (NCCR) in Structural Biology and by grant number 200020-137827 of the Swiss National Science Foundation, and by grant number 228076 of the European Research Council, which is gratefully acknowledged.

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Authors and Affiliations

  1. Laboratory of Physical Chemistry, ETH Zurich, 8093, Zurich, Switzerland

    Sereina Riniker & Wilfred F. van Gunsteren

  2. Laboratory of Organic Chemistry, ETH Zurich, 8093, Zurich, Switzerland

    Luzi J. Barandun & François Diederich

  3. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

    Oliver Krämer & Andreas Steffen

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  1. Sereina Riniker
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  6. Wilfred F. van Gunsteren
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Correspondence to Wilfred F. van Gunsteren.

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Riniker, S., Barandun, L.J., Diederich, F. et al. Free enthalpies of replacing water molecules in protein binding pockets. J Comput Aided Mol Des 26, 1293–1309 (2012). https://doi.org/10.1007/s10822-012-9620-8

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