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Strong and Weak Hydrogen Bonds in Protein–Ligand Recognition

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Journal of the Indian Institute of Science Aims and scope

Abstract

The hydrogen bond has justifiably been termed the ‘master key of molecular recognition’. It is an interaction that is weaker than the covalent bond and stronger than the van der Waals interaction. The ubiquity and flexibility of hydrogen bonds make them the most important physical interaction in systems of biomolecules in aqueous solution. Hydrogen bonding plays a significant role in many chemical and biological processes, including ligand binding and enzyme catalysis. In biological processes, both specificity and reversibility are important. Weaker interactions can be made and broken more easily than stronger interactions. In this context, it is of interest to assess the relative significance of strong and weak interactions in the macromolecular recognition processes. Is protein–ligand binding governed by conventional, that is, electrostatic N–H…O and O–H…O hydrogen bonds, or do weaker interactions with a greater dispersive component such as C–H…O hydrogen bonds also play a role? If so, to what extent are they significant? Most proteins, involving as they do, main chains, side chains, and differently bound forms of water, do not really have a static fixed structure, but rather have a dynamic, breathing nature. This tendency may to some extent be lessened by the ligands which are small molecules, but in the end, it is reasonable to expect that the strong and weak hydrogen bonds inside the protein and also at the protein–ligand interface will also have dynamic character; arguably, the weaker the hydrogen bond, the greater its dynamic character. These are often central to the much debated mechanisms of binding such as conformational selection and induced fit. All protein–ligand interactions must compete with interactions with water; both the protein and the ligand are solvated before complexation and lose their solvation shell on complex formation. Conversely, the entropic cost of trapping highly mobile water molecules in the binding site is large. However, in favorable cases, these losses are suitably compensated by the enthalpic gain resulting from water-mediated hydrogen bonds. In effect, the enthalpy–entropy balance is a fine one, and for a water molecule to be able to contribute to binding affinity, it has to be in a binding site that provides the maximum number of hydrogen-bond partners at the optimum distance and orientation. In summary, hydrogen bonds are crucial to the recognition of ligands by proteins. Integration of knowledge gained from more high-quality protein–ligand structures into theoretical and computational molecular models will be an exciting challenge in the coming years.

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References

  1. Desiraju GR (2011) A bond by any other name. Angew Chem Int Ed Engl 35:52–59. https://doi.org/10.1002/anie.201002960

    Article  CAS  Google Scholar 

  2. Desiraju GR, Steiner T (1999) The weak hydrogen bond in structural chemistry and biology. Oxford University Press, Oxford. https://doi.org/10.1093/acprof:oso/9780198509707.001.0001

    Book  Google Scholar 

  3. Jeffrey GA, Saenger W (1991) Hydrogen bonding in biological structures. Springer, Berlin. https://doi.org/10.1007/978-3-642-85135-3

    Book  Google Scholar 

  4. Desiraju GR (1995) Supramolecular synthons in crystal engineering—a new organic-synthesis. Angew Chem Int Ed 34:2311–2327. https://doi.org/10.1002/anie.199523111

    Article  CAS  Google Scholar 

  5. Glusker JP (1998) Directional aspects of intermolecular interactions. In: Weber E (ed) Topics in current chemistry: design of organic solids. Springer, Berlin, pp 1–56. https://doi.org/10.1007/3-540-69178-2_1

    Chapter  Google Scholar 

  6. Williams MA, Ladbury JE (2003) Hydrogen bonds in protein-ligand complexes. In: Böhm H-J, Schneider G (eds) Protein-ligand interactions: from molecular recognition to drug design. Wiley, Hoboken, pp 137–161. https://doi.org/10.1002/9783527610754.pl02

    Chapter  Google Scholar 

  7. Sarkhel S, Desiraju GR (2004) N–H…O, O–H…O, and C–H…O Hydrogen bonds in protein–ligand complexes: strong and weak interactions in molecular recognition. Proteins 54:247–259. https://doi.org/10.1002/prot.10567

    Article  CAS  Google Scholar 

  8. Williams DH, Stephens E, O’Brien DP, Zhou M (2004) Understanding noncovalent interactions: ligand binding energy and catalytic efficiency from ligand-induced reductions in motion within receptors and, enzymes. Angew Chem Int Ed 43:6596–6616. https://doi.org/10.1002/anie.200300644

    Article  CAS  Google Scholar 

  9. Gandhi R, Pillai O, Thilagavathi R, Gopalakrishnan B, Kaul CL, Panchagnula R (2002) Characterisation of azithromycin hydrates. Eur J Pharm Sci 16:175–184. https://doi.org/10.1016/S0928-0987(02)00087-8

    Article  CAS  Google Scholar 

  10. Connelly PR, Snyder PW, Zhang Y, McClain B, Quinn BP, Johnston S, Medek A, Tanoury J, Griffith J, Walters WP, Dokou E, Knezic D, Bransford P (2015) The potency–insolubility conundrum in pharmaceuticals: mechanism and solution for hepatitis C protease inhibitors. Biophys Chem 196:100–108. https://doi.org/10.1016/j.bpc.2014.08.008

    Article  CAS  Google Scholar 

  11. Sanphui P, Rajput L, Gopi SP, Desiraju GR (2016) New multi-component solid forms of an anti-cancer drug erlotinib: role of auxiliary interactions in determining a preferred conformation. Acta Crystallogr Sect B 72:291–300. https://doi.org/10.1107/s2052520616003607

    Article  CAS  Google Scholar 

  12. Desiraju GR (2002) Hydrogen bridges in crystal engineering: interactions without borders. Acc Chem Res 35:565–573. https://doi.org/10.1021/ar950135n

    Article  CAS  Google Scholar 

  13. Sutor DJ (1962) The C-H…O hydrogen bond in crystals. Nature 195:68–69

    Article  CAS  Google Scholar 

  14. Sutor DJ (1963) Evidence for the existence of C–H…O hydrogen bonds in crystals. J Chem Soc 1105–1110. https://doi.org/10.1039/jr9630001105

    Article  CAS  Google Scholar 

  15. Taylor R, Kennard O (1982) Crystallographic evidence for the existence of C–H…O, C–H…N and C–H…Cl hydrogen bonds. J Am Chem Soc 104:5063–5070. https://doi.org/10.1021/ja00383a012

    Article  CAS  Google Scholar 

  16. Extance A (2019) The forgotten female crystallographer who discovered C–H…O bonds. Chem World. https://www.chemistryworld.com/features/the-forgotten-female-crystallographer-who-discovered-cho-bonds/3010324.article

  17. Horowitz S, Trievel R, Scheiner S, Schwalbe C (2019) Do you know about C–H…O? Chem World. https://www.chemistryworld.com/opinion/do-you-know-about-cho/3010705.article

  18. Derewenda ZS, Lee L, Derewenda U (1995) The occurrence of C–H…O hydrogen bonds in proteins. J Mol Biol 252:248–262. https://doi.org/10.1006/jmbi.1995.0492

    Article  CAS  Google Scholar 

  19. Wahl MC, Sundaralingam M (1997) C–H…O hydrogen bonding in biology. Trends Biochem Sci 22:97–102. https://doi.org/10.1016/s0968-0004(97)01004-9

    Article  CAS  Google Scholar 

  20. Steiner T (1995) Water molecules which apparently accept no hydrogen bonds are systematically involved in C-H…O interactions. Acta Crystallogr Sect D 51:93–97. https://doi.org/10.1107/S0907444994007614

    Article  CAS  Google Scholar 

  21. Yesselman JD, Horowitz S, Brooks CL III, Trievel RC (2015) Frequent side chain methyl carbon-oxygen hydrogen bonding in proteins revealed by computational and stereochemical analysis of neutron structures. Proteins 83:403–410. https://doi.org/10.1002/prot.24724

    Article  CAS  Google Scholar 

  22. Castellano RK (2004) Progress toward understanding the nature and function of C-H…O interactions. Curr Org Chem 8:845–865. https://doi.org/10.2174/1385272043370384

    Article  CAS  Google Scholar 

  23. Fabiola GF, Krishnaswamy S, Nagarajan V, Pattabhi V (1997) C–H…O hydrogen bonds in β-sheets. Acta Crystallogr D 53:316–320. https://doi.org/10.1107/S0907444997000383

    Article  CAS  Google Scholar 

  24. Bhattacharyya R, Chakrabarti P (2003) Stereospecific interactions of proline residues in protein structures and complexes. J Mol Biol 331:925. https://doi.org/10.1016/s0022-2836(03)00759-9

    Article  CAS  Google Scholar 

  25. Desiraju GR, Sharma CVKM (1991) C–H…O hydrogen-bonding and topochemistry in crystalline 3,5-dinitrocinnamic acid and its 1–1 donor-acceptor complex with 2,5-dimethoxycinnamic acid. J Chem Soc Chem Commun. https://doi.org/10.1039/c39910001239

    Article  Google Scholar 

  26. Viswamitra MA, Radhakrishnan R, Bandekar J, Desiraju GR (1993) Evidence for O–H…C and N–H…C hydrogen-bonding in crystalline alkynes, alkenes, and aromatics. J Am Chem Soc 115:4868–4869. https://doi.org/10.1021/ja00064a055

    Article  CAS  Google Scholar 

  27. Thallapally PK, Katz AK, Carrell HL, Desiraju GR (2002) Unusually long cooperative chain of seven hydrogen bonds. An alternative packing type for symmetrical phenols. Chem Commun. https://doi.org/10.1039/b110036j

    Article  Google Scholar 

  28. Steiner T, Koellner G (2001) Hydrogen bonds with π-acceptors in proteins: frequencies and role in stabilizing local 3D structures. J Mol Biol 305:535–557. https://doi.org/10.1006/jmbi.2000.4301

    Article  CAS  Google Scholar 

  29. Desiraju GR (2005) C-H…O and other weak hydrogen bonds. From crystal engineering to virtual screening. Chem Commun. https://doi.org/10.1039/b504372g

    Article  Google Scholar 

  30. Panigrahi SK, Desiraju GR (2007) Strong and weak hydrogen bonds in the protein–ligand interface. Proteins 67:128–141. https://doi.org/10.1002/prot.21253

    Article  CAS  Google Scholar 

  31. Lipinski CA, Lombardo F, Dominy BW, Feeney PL (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 23:3–25. https://doi.org/10.1016/S0169-409X(96),00423-1

    Article  CAS  Google Scholar 

  32. Pierce AC, Sandretto KL, Bemis GW (2002) Kinase inhibitors and the case for C–H…O hydrogen bonds in protein–ligand binding. Proteins 49:567–576. https://doi.org/10.1002/prot.10259

    Article  CAS  Google Scholar 

  33. Adrian JC, Wilcox CS (1992) General effects of binding-site water exclusion on hydrogen-bond based molecular recognition systems—a closed binding-site is less affected by environmental-changes than an open site. J Am Chem Soc 114:1398. https://doi.org/10.1021/ja00030a040

    Article  CAS  Google Scholar 

  34. Berkovitch-Yellin Z, Leiserowitz L (1984) The role played by C-H…O and C–H…N interactions in determining molecular packing and conformation. Acta Crystallogr Sect B 40:159–165. https://doi.org/10.1107/s0108768194012061

    Article  Google Scholar 

  35. Anthony A, Jaskolski M, Nangia A, Desiraju GR (1998) Isostructurality in crystalline oxa-androgens: a case of C-H…O and C–H…O interaction mimicry and solid solution formation. Chem Commun. https://doi.org/10.1039/a806607h

    Article  Google Scholar 

  36. Thakur TS, Azim Y, Srinu T, Desiraju GR (2010) N–H…O and C–H…O interaction mimicry in the 1:1 molecular complexes of 5,5-diethylbarbituric acid with urea and acetamide. Curr Sci 98:793–802

    CAS  Google Scholar 

  37. Quiocho FA (1996) Atomic basis of the exquisite specificity of phosphate and sulfate transport receptors. Kidney Int 49:943–946

    Article  CAS  Google Scholar 

  38. Klaholz BP, Moras D (2002) C–H…O hydrogen bonds in the nuclear receptor RAR—a potential tool for drug selectivity. Structure 10:1197–1204. https://doi.org/10.1016/S0969-2126(02),00828-6

    Article  CAS  Google Scholar 

  39. Jiang L, Lai L (2002) C–H…O hydrogen bonds at the protein–protein interfaces. J Biol Chem 277:37732–37740. https://doi.org/10.1074/jbc.M204514200

    Article  CAS  Google Scholar 

  40. Aparna V, Rambabu G, Panigrahi SK, Sarma JARP, Desiraju GR (2005) Virtual screening of 4-anilinoquinazoline analogues as egfr kinase inhibitors: importance of hydrogen bonds in the evaluation of poses and scoring functions. J Chem Inf Model 45:725–738. https://doi.org/10.1021/ci049676u

    Article  CAS  Google Scholar 

  41. Gopalakrishnan B, Aparna V, Jeevan J, Ravi M, Desiraju GR (2005) A virtual screening approach for thymidine monophosphate kinase inhibitors as antitubercular agents based on docking and pharmacophore models. J Chem Inf Model 45:1101–1108. https://doi.org/10.1021/ci050064z

    Article  CAS  Google Scholar 

  42. Gruenberg S, Stubbs MT, Klebe G (2002) Successful virtual screening for novel inhibitors of human carbonic anhydrase: strategy and experimental confirmation. J Med Chem 45:3588–3602. https://doi.org/10.1021/jm011112j

    Article  CAS  Google Scholar 

  43. Lyne PD (2002) Structure-based virtual screening: an overview. Drug Discov Today 7:1047–1055. https://doi.org/10.1016/s1359-6446(02)02483-2

    Article  CAS  Google Scholar 

  44. Bleicher KH, Bohm H-J, Muller K, Alanine AI (2003) Hit and lead generation: beyond high-throughput screening. Nat Rev Drug Discovery 2:369–378. https://doi.org/10.1038/nrd1086

    Article  CAS  Google Scholar 

  45. Stamos J, Silwkowski MX, Eigenbrot C (2002) Structure of the epidermal growth factor receptor kinase domain alone and in the complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 48:46265–46272. https://doi.org/10.1074/jbc.M207135200

    Article  CAS  Google Scholar 

  46. Auffinger P, Hays FA, Westhof E, Ho PS (2004) Halogen bonds in biological molecules. Proc Natl Acad Sci USA 101:16789–16794. https://doi.org/10.1073/pnas.0407607101

    Article  CAS  Google Scholar 

  47. Shaw N, Cheng C, Tempel W, Chang J, Ng J, Wang X-Y, Perrett S, Rose J, Rao Z, Wang B-C, Liu Z-J (2007) (NZ)CH…O Contacts assist crystallization of a ParB-like nuclease. BMC Struct Biol 7:46. https://doi.org/10.1002/pro.420

    Article  CAS  Google Scholar 

  48. Misra P, Chakrabarti R, Vikramadithyan RK, Gopalakrishnan B, Suresh J, Jagadheshan H, Cynthia G, Rajjak A, Kashireddy P, Yu S, Surapureddi S, Qi C, Zhu Y-J, Rao MS, Reddy JK, Rajagopalan R (2003) PAT5A: a partial agonist of peroxisome proliferator-activated receptor is a potent antidiabetic thiazolidinedione yet weakly adipogenic. J Pharm Exp Ther 306:763–771. https://doi.org/10.1124/jpet.103.049791

    Article  CAS  Google Scholar 

  49. Arunan E, Desiraju GR, Klein RA, Sadlej J, Scheiner S, Alkorta I, Clary DC, Crabtree RH, Dannenberg JJ, Hobza P, Kjaergaard HG, Legon AC, Mennucci B, Nesbitt DJ (2011) Defining the hydrogen bond: an account (IUPAC technical report). Pure Appl Chem 83:1619–1636. https://doi.org/10.1351/PAC-REP-10-01-01

    Article  CAS  Google Scholar 

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Acknowledgements

GRD thanks the DST for the award of a J. C. Bose fellowship (SR/S2/JCB-18/2006).

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Correspondence to Gopalakrishnan Bulusu or Gautam R. Desiraju.

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Bulusu, G., Desiraju, G.R. Strong and Weak Hydrogen Bonds in Protein–Ligand Recognition. J Indian Inst Sci 100, 31–41 (2020). https://doi.org/10.1007/s41745-019-00141-9

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