3imj Citations

Thermodynamic and structural effects of conformational constraints in protein-ligand interactions. Entropic paradoxy associated with ligand preorganization.

J. Am. Chem. Soc. 131 16758-70 (2009)
Related entries: 3in7, 3kfj, 3in8, 3imd

Cited: 40 times
EuropePMC logo PMID: 19886660


Succinate- and cyclopropane-derived phosphotyrosine (pY) replacements were incorporated into a series of Grb2 SH2 binding ligands wherein the pY+1 residue was varied to determine explicitly how variations in ligand preorganization affect binding energetics and structure. The complexes of these ligands with the Grb2 SH2 domain were examined in a series of thermodynamic and structural investigations using isothermal titration calorimetry and X-ray crystallography. The binding enthalpies for all ligands were favorable, and although binding entropies for all ligands having a hydrophobic residue at the pY+1 site were favorable, binding entropies for those having a hydrophilic residue at this site were unfavorable. Preorganized ligands generally bound with more favorable Gibbs energies than their flexible controls, but this increased affinity was the consequence of relatively more favorable binding enthalpies. Unexpectedly, binding entropies of the constrained ligands were uniformly disfavored relative to their flexible controls, demonstrating that the widely held belief that ligand preorganization should result in an entropic advantage is not necessarily true. Crystallographic studies of complexes of several flexible and constrained ligands having the same amino acid at the pY+1 position revealed extensive similarities, but there were some notable differences. There are a greater number of direct polar contacts in complexes of the constrained ligands that correlate qualitatively with their more favorable binding enthalpies and Gibbs energies. There are more single water-mediated contacts between the domain and the flexible ligand of each pair; although fixing water molecules at a protein-ligand interface is commonly viewed as entropically unfavorable, entropies for forming these complexes are favored relative to those of their constrained counterparts. Crystallographic b-factors in the complexes of constrained ligands are greater than those of their flexible counterparts, an observation that seems inconsistent with our finding that entropies for forming complexes of flexible ligands are relatively more favorable. This systematic study highlights the profound challenges and complexities associated with predicting how structural changes in a ligand will affect enthalpies, entropies, and structure in protein-ligand interactions.

Articles - 3imj mentioned but not cited (2)

  1. Binding of flexible and constrained ligands to the Grb2 SH2 domain: structural effects of ligand preorganization. Clements JH, DeLorbe JE, Benfield AP, Martin SF. Acta Crystallogr. D Biol. Crystallogr. 66 1101-1115 (2010)
  2. Structural and functional analysis of betaine aldehyde dehydrogenase from Staphylococcus aureus. Halavaty AS, Rich RL, Chen C, Joo JC, Minasov G, Dubrovska I, Winsor JR, Myszka DG, Duban M, Shuvalova L, Yakunin AF, Anderson WF. Acta Crystallogr. D Biol. Crystallogr. 71 1159-1175 (2015)

Reviews citing this publication (7)

  1. Progress towards the development of SH2 domain inhibitors. Kraskouskaya D, Duodu E, Arpin CC, Gunning PT. Chem Soc Rev 42 3337-3370 (2013)
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  3. Thermodynamics of ligand binding and efficiency. Reynolds CH, Holloway MK. ACS Med Chem Lett 2 433-437 (2011)
  4. Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions. Delorbe JE, Clements JH, Whiddon BB, Martin SF. ACS Med Chem Lett 1 448-452 (2010)
  5. OpenStructure: a flexible software framework for computational structural biology. Biasini M, Mariani V, Haas J, Scheuber S, Schenk AD, Schwede T, Philippsen A. Bioinformatics 26 2626-2628 (2010)
  6. Constraining binding hot spots: NMR and molecular dynamics simulations provide a structural explanation for enthalpy-entropy compensation in SH2-ligand binding. Ward JM, Gorenstein NM, Tian J, Martin SF, Post CB. J. Am. Chem. Soc. 132 11058-11070 (2010)
  7. Bridging Calorimetry and Simulation through Precise Calculations of Cucurbituril-Guest Binding Enthalpies. Fenley AT, Henriksen NM, Muddana HS, Gilson MK. J Chem Theory Comput 10 4069-4078 (2014)
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  9. Current and emerging opportunities for molecular simulations in structure-based drug design. Michel J. Phys Chem Chem Phys 16 4465-4477 (2014)
  10. Sialyl Lewis(x): a "pre-organized water oligomer"? Binder FP, Lemme K, Preston RC, Ernst B. Angew. Chem. Int. Ed. Engl. 51 7327-7331 (2012)
  11. Computational Calorimetry: High-Precision Calculation of Host-Guest Binding Thermodynamics. Henriksen NM, Fenley AT, Gilson MK. J Chem Theory Comput 11 4377-4394 (2015)
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  13. The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides. Kumar EA, Chen Q, Kizhake S, Kolar C, Kang M, Chang CE, Borgstahl GE, Natarajan A. Sci Rep 3 1639 (2013)
  14. FimH antagonists: structure-activity and structure-property relationships for biphenyl α-D-mannopyranosides. Pang L, Kleeb S, Lemme K, Rabbani S, Scharenberg M, Zalewski A, Schädler F, Schwardt O, Ernst B. ChemMedChem 7 1404-1422 (2012)
  15. (E)-alkene and ethylene isosteres substantially alter the hydrogen-bonding network in class II MHC A(q)/glycopeptide complexes and affect T-cell recognition. Andersson IE, Batsalova T, Haag S, Dzhambazov B, Holmdahl R, Kihlberg J, Linusson A. J. Am. Chem. Soc. 133 14368-14378 (2011)
  16. Relative Binding Enthalpies from Molecular Dynamics Simulations Using a Direct Method. Roy A, Hua DP, Ward JM, Post CB. J Chem Theory Comput 10 2759-2768 (2014)
  17. Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase. Gallicchio E. Comput Mol Biosci 2 7-22 (2012)
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  19. Similar but different: thermodynamic and structural characterization of a pair of enantiomers binding to acetylcholinesterase. Berg L, Niemiec MS, Qian W, Andersson CD, Wittung-Stafshede P, Ekström F, Linusson A. Angew. Chem. Int. Ed. Engl. 51 12716-12720 (2012)
  20. Characterization of Promiscuous Binding of Phosphor Ligands to Breast-Cancer-Gene 1 (BRCA1) C-Terminal (BRCT): Molecular Dynamics, Free Energy, Entropy and Inhibitor Design. You W, Huang YM, Kizhake S, Natarajan A, Chang CE. PLoS Comput. Biol. 12 e1005057 (2016)
  21. Cyclodextrin-templated porphyrin nanorings. Liu P, Neuhaus P, Kondratuk DV, Balaban TS, Anderson HL. Angew. Chem. Int. Ed. Engl. 53 7770-7773 (2014)
  22. Protein-ligand interactions: probing the energetics of a putative cation-π interaction. Myslinski JM, Clements JH, Martin SF. Bioorg. Med. Chem. Lett. 24 3164-3167 (2014)
  23. Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain. Myslinski JM, Clements JH, Delorbe JE, Martin SF. ACS Med Chem Lett 4 (2013)
  24. Conformational restriction approach to β-secretase (BACE1) inhibitors III: effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations. Yonezawa S, Fujiwara K, Yamamoto T, Hattori K, Yamakawa H, Muto C, Hosono M, Tanaka Y, Nakano T, Takemoto H, Arisawa M, Shuto S. Bioorg. Med. Chem. 21 6506-6522 (2013)
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  26. Design and synthesis of a potential SH2 domain inhibitor bearing a stereodiversified 1,4-cis-enediol scaffold. Marian C, Huang R, Borch RF. Tetrahedron 67 10216-10221 (2011)
  27. Boosting Affinity by Correct Ligand Preorganization for the S2 Pocket of Thrombin: A Study by Isothermal Titration Calorimetry, Molecular Dynamics, and High-Resolution Crystal Structures. Rühmann EH, Rupp M, Betz M, Heine A, Klebe G. ChemMedChem 11 309-319 (2016)
  28. Cyclopropane-Based Peptidomimetics Mimicking Wide-Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization. Mizuno A, Kameda T, Kuwahara T, Endoh H, Ito Y, Yamada S, Hasegawa K, Yamano A, Watanabe M, Arisawa M, Shuto S. Chemistry (2016)
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  31. Synthesis and conformational analysis of peptides embodying 2,3-methanopipecolic acids. Ricci L, Sernissi L, Scarpi D, Bianchini F, Contini A, Occhiato EG. Org. Biomol. Chem. 15 6826-6836 (2017)

Related citations provided by authors (1)

  1. Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein-Ligand Interactions. Benfield AP, Teresk MG, Plake HR, DeLorbe JE, Millspaugh LE, Martin SF Angew. Chem. Int. Ed. Engl. 45 6830-6835 (2006)