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Halogenated benzenes bound within a non-polar cavity in T4 lysozyme provide examples of I...S and I...Se halogen-bonding.

Liu L, Baase WA, Matthews BW
J Mol Biol 385 595-605 (2009)
Related entries: 3dmx, 3dmz, 3dn0, 3dn1, 3dn2, 3dn3, 3dn4, 3dn6, 3dn8, 3dna

Cited: 40 times
EuropePMC logo PMID: 19014950

Abstract

We showed earlier that the mutation of Leu99 to alanine in bacteriophage T4 lysozyme creates an internal cavity of volume approximately 150 A(3) that binds benzene and a variety of other ligands. As such, this cavity provides an excellent target to study protein-ligand interaction. Here, we use low-temperature crystallography and related techniques to analyze the binding of halogen-incorporated benzenes typified by C(6)F(5)X, where X=H, F, Cl, Br or I, and C(6)H(5)X, where X=H or I was also studied. Because of the increased electron density of fluorine relative to hydrogen, the geometry of binding of the fluoro compounds can often be determined more precisely than their hydrogen-containing analogs. All of the ligands bind in essentially the same plane but the center of the phenyl ring can translate by up to 1.2 A. In no case does the ligand rotate freely within the cavity. The walls of the cavity consist predominantly of hydrocarbon atoms, and in several cases it appears that van der Waals interactions define the geometry of binding. In comparing the smallest with the largest ligand, the cavity volume increases from 181 A(3) to 245 A(3). This shows that the protein is flexible and adapts to the size and shape of the ligand. There is a remarkably close contact of 3.0 A between the iodine atom on C(6)F(5)I and the sulfur or selenium atom of Met or SeMet102. This interaction is 1.0 A less than the sum of the van der Waals radii and is a clear example of a so-called halogen bond. Notwithstanding this close approach, the increase in binding energy for the halogen bond relative to a van der Waals contact is estimated to be only about 0.5-0.7 kcal/mol.

Articles - 3dmv mentioned but not cited (14)

  1. Solution structure of a minor and transiently formed state of a T4 lysozyme mutant. Bouvignies G, Vallurupalli P, Hansen DF, Correia BE, Lange O, Bah A, Vernon RM, Dahlquist FW, Baker D, Kay LE. Nature 477 111-114 (2011)
  2. NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers. Sekhar A, Kay LE. Proc Natl Acad Sci U S A 110 12867-12874 (2013)
  3. Mapping transiently formed and sparsely populated conformations on a complex energy landscape. Wang Y, Papaleo E, Lindorff-Larsen K. Elife 5 e17505 (2016)
  4. DEER-PREdict: Software for efficient calculation of spin-labeling EPR and NMR data from conformational ensembles. Tesei G, Martins JM, Kunze MBA, Wang Y, Crehuet R, Lindorff-Larsen K. PLoS Comput Biol 17 e1008551 (2021)
  5. Structure-relaxation mechanism for the response of T4 lysozyme cavity mutants to hydrostatic pressure. Lerch MT, López CJ, Yang Z, Kreitman MJ, Horwitz J, Hubbell WL. Proc Natl Acad Sci U S A 112 E2437-46 (2015)
  6. Atomic resolution mechanism of ligand binding to a solvent inaccessible cavity in T4 lysozyme. Mondal J, Ahalawat N, Pandit S, Kay LE, Vallurupalli P. PLoS Comput Biol 14 e1006180 (2018)
  7. Atomistic picture of conformational exchange in a T4 lysozyme cavity mutant: an experiment-guided molecular dynamics study. Vallurupalli P, Chakrabarti N, Pomès R, Kay LE. Chem Sci 7 3602-3613 (2016)
  8. Dynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses. Toyama Y, Kano H, Mase Y, Yokogawa M, Osawa M, Shimada I. Nat Commun 8 14523 (2017)
  9. Determining rotational dynamics of the guanidino group of arginine side chains in proteins by carbon-detected NMR. Gerecht K, Figueiredo AM, Hansen DF. Chem Commun (Camb) 53 10062-10065 (2017)
  10. Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A. Schiffer JM, Feher VA, Malmstrom RD, Sida R, Amaro RE. Biophys J 111 1631-1640 (2016)
  11. Mechanisms for Benzene Dissociation through the Excited State of T4 Lysozyme L99A Mutant. Feher VA, Schiffer JM, Mermelstein DJ, Mih N, Pierce LCT, McCammon JA, Amaro RE. Biophys J 116 205-214 (2019)
  12. Ligand Binding Path Sampling Based on Parallel Cascade Selection Molecular Dynamics: LB-PaCS-MD. Aida H, Shigeta Y, Harada R. Materials (Basel) 15 1490 (2022)
  13. On identifying collective displacements in apo-proteins that reveal eventual binding pathways. Dube D, Ahalawat N, Khandelia H, Mondal J, Sengupta S. PLoS Comput Biol 15 e1006665 (2019)
  14. Automated Path Searching Reveals the Mechanism of Hydrolysis Enhancement by T4 Lysozyme Mutants. Xi K, Zhu L. Int J Mol Sci 23 14628 (2022)


Reviews citing this publication (5)

  1. The Halogen Bond. Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem Rev 116 2478-2601 (2016)
  2. Halogen bonding in halocarbon-protein complexes: a structural survey. Parisini E, Metrangolo P, Pilati T, Resnati G, Terraneo G. Chem Soc Rev 40 2267-2278 (2011)
  3. Lessons from the lysozyme of phage T4. Baase WA, Liu L, Tronrud DE, Matthews BW. Protein Sci 19 631-641 (2010)
  4. Halogen bonding for rational drug design and new drug discovery. Lu Y, Liu Y, Xu Z, Li H, Liu H, Zhu W. Expert Opin Drug Discov 7 375-383 (2012)
  5. A Halogen Bonding Perspective on Iodothyronine Deiodinase Activity. Marsan ES, Bayse CA. Molecules 25 E1328 (2020)

Articles citing this publication (21)

  1. Halogen bonding: an interim discussion. Politzer P, Murray JS. Chemphyschem 14 278-294 (2013)
  2. Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design. Lu Y, Wang Y, Zhu W. Phys Chem Chem Phys 12 4543-4551 (2010)
  3. Absolute binding free energy calculations: on the accuracy of computational scoring of protein-ligand interactions. Singh N, Warshel A. Proteins 78 1705-1723 (2010)
  4. Fluorine-protein interactions and ¹⁹F NMR isotropic chemical shifts: An empirical correlation with implications for drug design. Dalvit C, Vulpetti A. ChemMedChem 6 104-114 (2011)
  5. Boron mimetics: 1,2-dihydro-1,2-azaborines bind inside a nonpolar cavity of T4 lysozyme. Liu L, Marwitz AJ, Matthews BW, Liu SY. Angew Chem Int Ed Engl 48 6817-6819 (2009)
  6. Halogen bonding to a divalent sulfur atom: an experimental study of the interactions of CF3X (X = Cl, Br, I) with dimethyl sulfide. Hauchecorne D, Moiana A, van der Veken BJ, Herrebout WA. Phys Chem Chem Phys 13 10204-10213 (2011)
  7. A comprehensive examination of the contributions to the binding entropy of protein-ligand complexes. Singh N, Warshel A. Proteins 78 1724-1735 (2010)
  8. Absolute Binding Free Energies between T4 Lysozyme and 141 Small Molecules: Calculations Based on Multiple Rigid Receptor Configurations. Xie B, Nguyen TH, Minh DDL. J Chem Theory Comput 13 2930-2944 (2017)
  9. Halogen-enriched fragment libraries as chemical probes for harnessing halogen bonding in fragment-based lead discovery. Zimmermann MO, Lange A, Wilcken R, Cieslik MB, Exner TE, Joerger AC, Koch P, Boeckler FM. Future Med Chem 6 617-639 (2014)
  10. Complementary halogen and hydrogen bonding: sulfur...iodine interactions and thioamide ribbons. Arman HD, Gieseking RL, Hanks TW, Pennington WT. Chem Commun (Camb) 46 1854-1856 (2010)
  11. Temperature artifacts in protein structures bias ligand-binding predictions. Bradford SYC, El Khoury L, Ge Y, Osato M, Mobley DL, Fischer M. Chem Sci 12 11275-11293 (2021)
  12. Could the "Janus-like" properties of the halobenzene CX bond (X=Cl, Br) be leveraged to enhance molecular recognition? El Hage K, Piquemal JP, Hobaika Z, Maroun RG, Gresh N. J Comput Chem 36 210-221 (2015)
  13. Multiquantum Chemical Exchange Saturation Transfer NMR to Quantify Symmetrical Exchange: Application to Rotational Dynamics of the Guanidinium Group in Arginine Side Chains. Karunanithy G, Reinstein J, Hansen DF. J Phys Chem Lett 11 5649-5654 (2020)
  14. Tetrameric architecture of an active phenol-bound form of the AAA+ transcriptional regulator DmpR. Park KH, Kim S, Lee SJ, Cho JE, Patil VV, Dumbrepatil AB, Song HN, Ahn WC, Joo C, Lee SG, Shingler V, Woo EJ. Nat Commun 11 2728 (2020)
  15. Vibrational Stark spectroscopy for assessing ligand-binding strengths in a protein. Mondal P, Meuwly M. Phys Chem Chem Phys 19 16131-16143 (2017)
  16. A cryospectroscopic infrared and Raman study of the CX⋯π halogen bonding motif: complexes of the CF3Cl, CF3Br, and CF3I with ethyne, propyne and 2-butyne. Nagels N, Herrebout WA. Spectrochim Acta A Mol Biomol Spectrosc 136 Pt A 16-26 (2015)
  17. Exchangeable deuterons introduce artifacts in amide 15N CEST experiments used to study protein conformational exchange. Tiwari VP, Pandit S, Vallurupalli P. J Biomol NMR 73 43-48 (2019)
  18. Measuring the signs of the methyl 1H chemical shift differences between major and 'invisible' minor protein conformational states using methyl 1H multi-quantum spectroscopy. Gopalan AB, Vallurupalli P. J Biomol NMR 70 187-202 (2018)
  19. Implicit ligand theory for relative binding free energies: II. An estimator based on control variates. Nguyen TH, Minh DDL. J Phys Commun 4 115010 (2020)
  20. Long-time-step molecular dynamics can retard simulation of protein-ligand recognition process. Sahil M, Sarkar S, Mondal J. Biophys J 122 802-816 (2023)
  21. Synthesis of 1,2-Azaborines and the Preparation of Their Protein Complexes with T4 Lysozyme Mutants. Lee H, Liu SY. J Vis Exp (2017)


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