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Effects of local protein environment on the binding of diatomic molecules to heme in myoglobins. DFT and dispersion-corrected DFT studies

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Abstract

The heme-AB binding energies (AB = CO, O2) in a wild-type myoglobin (Mb) and two mutants (H64L, V68N) of Mb have been investigated in detail with both DFT and dispersion-corrected DFT methods, where H64L and V68N represent two different, opposite situations. Several dispersion correction approaches were tested in the calculations. The effects of the local protein environment were accounted for by including the five nearest surrounding residues in the calculated systems. The specific role of histidine-64 in the distal pocket was examined in more detail in this study than in other studies in the literature. Although the present calculated results do not change the previous conclusion that the hydrogen bonding by the distal histidine-64 residue plays a major role in the O2/CO discrimination by Mb, more details about the interaction between the protein environment and the bound ligand have been revealed in this study by comparing the binding energies of AB to a porphyrin and the various myoglobins. The changes in the experimental binding energies from one system to another are well reproduced by the calculations. Without constraints on the residues in geometry optimization, the dispersion correction is necessary, since it improves the calculated structures and energetic results significantly.

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Notes

  1. In fact, we do not need to consider BSSE in the present calculations at all because we do not calculate intermolecular binding energies in this work.

  2. The crystal coordinates are not the experimental raw data; they are a product of an involved series of model building, crystallographic refinement, manual examination, and rebuilding, possibly involving mistakes in interpretation.

  3. Previous calculations with all-electron method (ref. [56]) or with an increased accuracy of the numerical integration (ref. [66]) could give FeP(4-EtIm)-AB binding energies which are somewhat larger than the present ones. Owing to error cancellations, the present calculated results are actually in closer agreement with experiment than the previous ones.

References

  1. Stryer L (1981) Biochemistry, 4th edn. Freeman, New York

    Google Scholar 

  2. Collman JP, Brauman JI, Halbert TR, Suslick KS (1976) Nature of O2 and CO binding to metalloporphyrins and heme proteins. Proc Natl Acad Sci USA 73:3333–3337

    Article  CAS  Google Scholar 

  3. Kuriyan J, Wilz S, Karplus M, Petsko GA (1986) X-ray structure and refinement of carbon- monoxy (Fe II)-myoglobin at 1.5 Å resolution. J Mol Biol 192:133–154

    Article  CAS  Google Scholar 

  4. Cheng X-D, Schoenborn BP (1991) Neutron diffraction study of carbonmonoxymyoglobin. J Mol Biol 220:381–399

    Article  CAS  Google Scholar 

  5. Kachalova GS, Popov AN, Bartunik HD (1999) A steric mechanism for inhibition of CO binding to heme proteins. Science 284:473–476

    Article  CAS  Google Scholar 

  6. Vojtechovsky J, Chu K, Berendzen J, Sweet RM, Schlichting I (1999) Crystal structures of myoglobin-ligand complexes at near-atomic resolution. Biophys J 77:2153–2174

    Article  CAS  Google Scholar 

  7. Lim M-H, Jackson TA, Anfinrud PA (1995) Binding of CO to myoglobin from a heme pocket docking site to form nearly linear Fe-C-O. Science 269:962–966

    Article  CAS  Google Scholar 

  8. Ivanov D, Sage JT, Keim M, Powell JR, Asher SA (1994) Determination of CO orientation in myoglobin by single-crystal infrared linear dichroism. J Am Chem Soc 116:4139–4140

    Article  CAS  Google Scholar 

  9. Kozlowski PM, Vogel KM, Zgierski MZ, Spiro TG (2001) Steric contributions to CO binding in heme proteins: a density functional analysis of FeCO vibrations and deformability. J Porph Phthal 5:312–322

    Article  CAS  Google Scholar 

  10. McMahon MT, deDios AC, Godbout N, Salzmann R, Laws DD, Le H-B, Havlin RH, Oldfield E (1998) An experimental and quantum chemical investigation of CO binding to heme proteins and model systems: a unified model based on 13C, 17O, and 57Fe nuclear magnetic resonance and 57Fe moessbauer and infrared spectroscopies. J Am Chem Soc 120:4784–4797

    Article  CAS  Google Scholar 

  11. Springer BA, Sligar SG, Olson JS, Phillips GN (1994) Mechanisms of ligand recognition in myoglobin. Chem Rev 94:699–714

    Article  CAS  Google Scholar 

  12. Phillips SEV, Schoenborn BP (1981) Neutron diffraction reveals oxygen-histidine hydrogen bond in oxymyoglobin. Nature 292:81–82

    Article  CAS  Google Scholar 

  13. Lukin JA, Simplaceanu V, Zou M, Ho NT, Ho C (2000) NMR reveals hydrogen bonds between oxygen and distal histidines in oxyhemoglobin. Proc Natl Acad Sci USA 97:10354–10358

    Article  CAS  Google Scholar 

  14. Sigfridsson E, Ryde U (1999) On the significance of hydrogen bonds for the discrimination between CO and O2 by myoglobin. J Biol Inorg Chem 4:99–110

    Article  CAS  Google Scholar 

  15. Sigfridsson E, Ryde U (2002) Theoretical study of the discrimination between O2 and CO by myoglobin. J Inorg Biochem 91:101–115

    Article  CAS  Google Scholar 

  16. Edwards WD, Weiner B, Zerner MC (1986) On the low-lying states and electronic spectroscopy of iron(II) porphine. J Am Chem Soc 108:2196–2204

    Article  CAS  Google Scholar 

  17. Waleh A, Ho N, Chantranupong L, Loew GH (1989) Electronic structure of nitrosyl ferrous heme complexes. J Am Chem Soc 111:2767–2772

    Article  CAS  Google Scholar 

  18. Case DA, Huynh BH, Karplus M (1979) Binding of oxygen and carbon monoxide to hemoglobin. An analysis of the ground and excited states. J Am Chem Soc 101:4433–4453

    Article  CAS  Google Scholar 

  19. Hoffmann R, Chen MML, Thorn DL (1977) Qualitative discussion of alternative coordination modes of diatomic ligands in transition metal complexes. Inorg Chem 16:503–511

    Article  CAS  Google Scholar 

  20. Rovira C, Kunc K, Hutter J, Ballone P, Parrinello M (1997) Equilibrium geometries and electronic structure of iron-porphyrin complexes: a density functional study. J Phys Chem A 101:8914–8925

    Article  CAS  Google Scholar 

  21. Rovira C, Parrinello M (1999) Factors influencing ligand-binding properties of heme models: a first principles study of picket-fence and protoheme complexes. Chem Eur J 5:250–262

    Article  CAS  Google Scholar 

  22. Vogel KM, Kozlowski PM, Zgierski MZ, Spiro TG (1999) Determinants of the FeXO (X = C, N, O) vibrational frequencies in heme adducts from experiment and density functional theory. J Am Chem Soc 121:9915–9921

    Article  CAS  Google Scholar 

  23. Vogel KM, Kozlowski PM, Zgierski MZ, Spiro TG (2000) Role of the axial ligand in heme- CO backbonding; DFT analysis of vibrational data. Inorg Chim Acta 297:11–17

    Article  CAS  Google Scholar 

  24. Rovira C, Parrinello M (2000) Harmonic and anharmonic dynamics of Fe-CO and Fe-O2 in heme models. Biophys J 78:93–100

    Article  CAS  Google Scholar 

  25. Rovira C, Schulze B, Eichinger M, Evanseck JD, Parrinello M (2001) Influence of the heme pocket conformation on the structure and vibrations of the Fe-CO bond in myoglobin: a QM/MM density functional study. Biophys J 81:435–445

    Article  CAS  Google Scholar 

  26. Blomberg LM, Blomberg MRA, Siegbahn PEM (2005) A theoretical study on the binding of O2, NO and CO to heme proteins. J Inorg Biochem 99:949–958

    Article  CAS  Google Scholar 

  27. De Angelis F, Jarzecki AA, Car R, Spiro TG (2005) Quantum chemical evaluation of protein control over heme ligation: CO/O2 discrimination in myoglobin. J Phys Chem B 109:3065–3070

    Article  Google Scholar 

  28. Strickland N, Mulholland AJ, Harvey JN (2006) The Fe-CO bond energy in myoglobin: a QM/MM study of the effect of tertiary structure. Biophys J 90:L27–L29

    Article  CAS  Google Scholar 

  29. Scherlis DA, Cococcioni M, Sit P, Marzari N (2007) Simulation of heme using DFT + U: a step toward accurate spin-state energetics. J Phys Chem B 111:7384–7391

    Article  CAS  Google Scholar 

  30. Strickland N, Harvey JN (2007) Spin-forbidden ligand binding to the ferrous-heme group: ab initio and DFT studies. J Phys Chem B 111:841–852

    Article  CAS  Google Scholar 

  31. Chen H, Ikeda-Saito M, Shaik S (2008) Nature of the Fe-O2 bonding in oxy-myoglobin: effect of the protein. J Am Chem Soc 130:14778–14790

    Article  CAS  Google Scholar 

  32. Siegbahn PEM, Blomberg MRA, Chen S-L (2010) Significant van der Waals effects in transition metal complexes. J Chem Theory Comput 6:2040–2044

    Article  CAS  Google Scholar 

  33. Cole DJ, O’Regan DD, Payne MC (2012) Ligand discrimination in myoglobin from linear-scaling DFT + U. J Phys Chem Lett 3:1448–1452

    Article  CAS  Google Scholar 

  34. Olson JS, Phillips GN (1997) Myoglobin discriminates between O2, NO, and CO by electrostatic interactions with the bound ligand. J Biol Inorg Chem 2:544–552

    Article  CAS  Google Scholar 

  35. Krzywda S, Murshudov GN, Brzozowski AM, Jaskolski M, Scott EE, Klizas SA, Gibson QH, Olson JS, Wilkinson AJ (1998) Stabilizing bound O2 in myoglobin by Valine68 (E11) to asparagine substitution. Biochemistry 37:15896–15907

    Article  CAS  Google Scholar 

  36. Draghi F, Miele AE, Travaglini-Allocatelli C, Vallone B, Brunori M, Gibson QH, Olson JS (2002) Controlling ligand binding in myoglobin by mutagenesis. J Biol Chem 277:7509–7519

    Article  CAS  Google Scholar 

  37. Coyle CM, Vogel KM, Rush TS, Kozlowski PM, Williams R, Spiro TG, Dou Y, Ikeda-Saito M, Olson JS, Zgierski MZ (2003) FeNO structure in distal pocket mutants of myoglobin based on resonance Raman spectroscopy. Biochemistry 42:4896–4903

    Article  CAS  Google Scholar 

  38. Kundu S, Blouin GC, Premer SA, Sarath G, Olson JS, Hargrove MS (2004) Tyrosine B10 inhibits stabilization of bound carbon monoxide and oxygen in soybean leghemoglobin. Biochemistry 43:6241–6252

    Article  CAS  Google Scholar 

  39. Chen O, Groh S, Liechty A, Ridge DP (1999) Binding of nitric oxide to iron(II) porphyrins: radiative association, blackbody infrared radiative dissociation and gas-phase association equilibrium. J Am Chem Soc 121:11910–11911

    Article  CAS  Google Scholar 

  40. Momenteau M, Reed CA (1994) Synthetic heme-dioxygen complexes. Chem Rev 94:659–698

    Article  CAS  Google Scholar 

  41. Spiro TG, Kozlowski PM (2001) Is the CO adduct of myoglobin bent, and does it matter? Acc Chem Res 34:137–144

    Article  CAS  Google Scholar 

  42. Jung Y, Head-Gordon M (2006) A fast correlated electronic structure method for computing interaction energies of large van der Waals complexes applied to the fullerene-porphyrin dimer. Phys Chem Chem Phys 8:2831–2840

    Article  CAS  Google Scholar 

  43. Sinnokrot MO, Sherrill CD (2006) High-accuracy quantum mechanical studies of pi-pi interactions in benzene dimers. J Phys Chem A 110:10656–10668

    Article  CAS  Google Scholar 

  44. Hesselmann A, Jansen G, Schütz M (2005) Density-functional theory-symmetry-adapted intermolecular perturbation theory with density fitting: a new efficient method to study intermolecular interaction energies. J Chem Phys 122:14103–14120

    Google Scholar 

  45. Grimme S (2004) Accurate description of van der Waals complexes by density functional theory including empirical corrections. J Comput Chem 25:1463–1473

    Article  CAS  Google Scholar 

  46. Riley KE, Pitonak M, Jurecka P, Hobza P (2010) Stabilization and structure calculations for noncovalent interactions in extended molecular systems based on wave function and density functional theories. Chem Rev 110:5023–5063

    Article  CAS  Google Scholar 

  47. Liao M-S, Huang M-J, Watts JD (2012) Assessment of dispersion corrections in DFT calculations on large biological systems. Mol Phys 110:3061–3076. doi:10.1080/00268976.2012.695811

    Article  CAS  Google Scholar 

  48. Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J Chem Phys 132:154104–1-25

    Article  Google Scholar 

  49. Grimme S, Ehrlich S, Goerigk L (2011) Effect of the damping function in dispersion corrected density functional theory. J Comput Chem 32:1456–1465

    Article  CAS  Google Scholar 

  50. Steinmann SN, Corminboeuf C (2011) Comprehensive benchmarking of a density- dependent dispersion correction. J Chem Theory Comput 7:3567–3577

    Article  CAS  Google Scholar 

  51. Springer BA, Egeberg KD, Slighar SG, Rohlfs RJ, Mathews AJ, Olson JC (1989) Discrimination between oxygen and carbon monoxide and inhibition of autooxidation by myoglobin. Site-directed mutagenesis of the distal histidine. J Biol Chem 264:3057–3060

    CAS  Google Scholar 

  52. Radon M, Pierloot K (2008) Binding of CO, NO, and O2 to heme by density functional and multireference ab initio calculations. J Phys Chem A 112:11824–11832

    Article  CAS  Google Scholar 

  53. Traylor TG, Stynes DV (1980) Isocyanide binding to chelated protoheme. Kinetic criteria for distal steric effects in hemoproteins. J Am Chem Soc 102:5938–5939

    Article  CAS  Google Scholar 

  54. Grimme S (2006) Semiempirical GGA-type density functional constructed with a long-range dispersion correction. J Comput Chem 27:1787–1799

    Article  CAS  Google Scholar 

  55. Liao M-S, Watts JD, Huang M-J (2009) Dispersion-corrected DFT calculations on C60-porphyrin complexes. Phys Chem Chem Phys 11:4365–4374

    Article  CAS  Google Scholar 

  56. Liao M-S, Huang M-J, Watts JD (2010) Iron porphyrins with different imidazole ligands – a theoretical comparative study. J Phys Chem A 114:9554–9569

    Article  CAS  Google Scholar 

  57. Quillin ML, Arduini RM, Olson JS, Phillips GN (1993) High-resolution crystal structures of distal histidine mutants of sperm whale myoglobin. J Mol Biol 234:140–155

    Article  CAS  Google Scholar 

  58. te Velde G, Bickelhaupt FM, van Gisbergen SJA, Fonseca-Guerra C, Baerends EJ, Snijders JG, Ziegler T (2001) Chemistry with ADF. J Comput Chem 22:931–967

    Article  Google Scholar 

  59. ADF2012.01. SCM, Theoretical Chemistry, Vrije Universiteit, Amsterdam, Netherlands. See also (http://www.scm.com)

  60. Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Phys Rev A 38:3098–3100

    Article  CAS  Google Scholar 

  61. Perdew JP (1986) Density-functional approximation for the correlation energy of the inhomogeneous electron gas. Phys Rev B 33:8822–8824

    Article  Google Scholar 

  62. Perdew JP, Burke K, Ernzerhof M (1996) Generalized gradient approximation made simple. Phys Rev Lett 77:3865–3868

    Article  CAS  Google Scholar 

  63. Zhang Y-K, Yang W-T (1998) Comment on “Generalized gradient approximation made simple”. Phys Rev Lett 80:890–890

    Article  CAS  Google Scholar 

  64. Becke AD (1993) Density-functional thermochemistry.3. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  65. Lee C, Yang WT, Parr RG (1988) Development of the colle-salvetti correlation-energy formula into a functional of the electron-density. Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  66. Liao M-S, Huang M-J, Watts JD (2011) FeP(Im)-AB bonding energies evaluated with a large number of density functionals (P = porphine, Im = imidazole, AB = CO, NO, and O2). Mol Phys 109:2035–2048

    Article  CAS  Google Scholar 

  67. Kannemann FO, Becke AD (2010) van der Waals interactions in density-functional theory: intermolecular complexes. J Chem Theory Comput 6:1081–1088

    Article  CAS  Google Scholar 

  68. Tang KT, Toennies JP (1984) An improved simple model for the van der Waals potential based on universal damping functions for the dispersion coefficients. J Chem Phys 80:3726–3741

    Article  CAS  Google Scholar 

  69. Barone V, Biczysko M, Pavone M (2008) The role of dispersion correction to DFT for modelling weakly bound molecular complexes in the ground and excited electronic states. Chem Phys 346:247–256

    Article  CAS  Google Scholar 

  70. Ziegler T, Tschinke V, Baerends EJ, Snijders JG, Ravenek W (1989) Calculation of bond energies in compounds of heavy elements by a quasi-relativistic approach. J Phys Chem 93:3050–3056

    Article  CAS  Google Scholar 

  71. Jameson GB, Molinaro FS, Ibers JA, Collman JP, Brauman JI, Rose E, Suslick KS (1980) Models for the active site of oxygen-binding hemoproteins. Dioxygen binding properties and the structures of (2-methylimidazole)-meso-tetra(alpha, alpha, alpha, alpha-o- pivalamidophenyl)porphyrinatoiron(II)-ethanol and its dioxygen adduct. J Am Chem Soc 102:3224–3237

    Article  CAS  Google Scholar 

  72. Chai J-D, Head-Gordon M (2008) Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections. Phys Chem Chem Phys 10:6615–6620

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by Award Number SC1-HL096018 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health (NIH). The ADF calculations were run on a QuantumCube™ QS32-2800C computer from Parallel Quantum Solutions, LLC.

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  1. Department of Chemistry, Jackson State University, Jackson, MS, 39217, USA

    Meng-Sheng Liao, Ming-Ju Huang & John D. Watts

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  1. Meng-Sheng Liao
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Correspondence to John D. Watts.

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Supplementary material

Damping functions in the various DFT + Edisp methods employed in this paper. Calculated structural parameters for the iron porphyrins [FeP(4-EtIm), FeP(4-EtIm)(AB)] and the various myoglobins [MbAB, H64L(AB), V68N(AB)] (AB = CO, O2), together with available experimental (X-ray) crystal structural data. Calculated relative energies for selected states of FeP(Im) with the B3LYP functional from the literature and in this work. BP and B3LYP calculated FeP(Im)-AB bonding energies from the literature and in this work. Comparison of the calculated energies (Ebind, ΔEbind) with DFT and various DFT + Edisp methods (−D1, −D3, −D3(BJ), -dDsC). (PDF 230 kb)

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Liao, MS., Huang, MJ. & Watts, J.D. Effects of local protein environment on the binding of diatomic molecules to heme in myoglobins. DFT and dispersion-corrected DFT studies. J Mol Model 19, 3307–3323 (2013). https://doi.org/10.1007/s00894-013-1864-2

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