Determination of acidic dissociation constants of L-phenylalanyl-glycine and L-alanyl-L-alanine in water using ab initio methods

Abstract

The acid dissociation constant is one of the fundamental properties of organic molecules. In this study, den- sity functional theory DFT calculations with B3LYP combined with 6-31+G d basis set were applied for determination of acidic dissociation constants of L-phenylalanyl-glycine and L-alanyl-L-alanine. An ab initio procedure for accurately calculating aqueous-phase pKa values of the L-phenylalanyl-glycine and L-alanyl- L-alanine is presented. Formation of intermolecular hydrogen bonds between the existent species and water has been analyzed using Tomasi’s method. In this way, it was determined that in alkaline aqueous solutions the cation, anion, and neutral species of L-phenylalanyl-glycine and L-alanyl-L-alanine are solvated with some molecules of water. Furthermore, the correlation between the pKa values of these dipeptides was investigated theoretically, and a comparable agreement was found with the experimental results.

Keywords

• Acidity constant,L-phenylalanyl-glycine,L-alanyl-L-alanine,solvation free energy,ab initio methods

L-fenilalanil-gilisin ve L-alanil-L-alaninin sudaki asidik ayrışma sabitlerinin ab initio yöntemleri ile belirlenmesi

Abstract

A sidik ayrışma sabiti organik bileşiklerin en temel özelliklerinden birisidir. Bu çalışmada, yoğunluk fonksiyon teori DFT hesaplamaları 6-31+G d ile B3LYP birleştirilmiş temel setler L-fenilalanil-glisin ve L-alanil-Lalaninin asidik ayrışma sabitlerinin belirlenmesinde uygulanmıştır. L-fenilalanil-glisin ve L-alanil-L-alaninin sulufaz pK değeri hesaplamaları için ab initio yöntemi sunulmuştur. Mevcut türler ve su arasında oluşan moleküller arası hidrojen bağlarının oluşumu Tomasi yöntemi kullanılarak analiz edilmiştir. Bu şekilde, su molekülleri ile solvate olmuş L-fenilalanil-glisin ve L-alanil-L-alaninin katyonu, anyon ve nötr türleri bazik sulu çözeltilerde belirlenmiştir. Ayrıca, bu dipeptidlerin pKa değerleri arasındaki ilişki teorik olarak incelenmiş ve kıyaslanabilir uyumlu deneysel sonuçlar bulunmuştur

Keywords

• Asitlik sabiti,L-fenilalanil-glisin,L-alanil-L-alanin,çözünme serbest enerjisi,ab initio yöntemleri

References

1. J.A. Getz, J.J. Rice, P.S. Daugherty, Protease-resistant peptide ligands from a knottin scaffold library, ACS Chem. Biol., 6 (2011) 837.
2. A. Catsch, A.E. Harmuth-Hoene, Pharmacology and therapeutic applications of agents used in heavy metal poisoning, Pharmacol. Ther, Part A. 1 (1976) 1.
3. M.D. Beachy, D. Chasman, R.B. Murphy, T.A. Halgren, R.A. Friesner, Accurate ab initio quantum chemical determination of the relative energetics of peptide conformations and assessment of empirical force fields, J. Am. Chem. Soc., 119 (1997) 5908.
4. M. Namazian, H. Heidary, Ab initio calculations of pKa values of some organic acids in aqueous solution, J. Mol. Struct. (Theochem), 620 (2003) 257.
5. H. Wan, J. Ulander, High-throughput pKa screening and prediction amenable for ADME profiling, Expert Opin. Drug. Metab. Toxicol., 2 (2006) 139.
6. I.A. Topol, I.A. Tawa, R A. Caldwell, M.A. Eissenstat, S.K. Burt, Acidity of organic molecules in the gas phase and in aqueous solvent, J. Phys. Chem. A, 104 (2000) 9619. 7. F. Ding, J.M. Smith, H. Wang, First-principles calculation of pKa values for organic acids in nonaqueous solution, J. Org. Chem., 74 (2009) 2679.
7. J.R. Pliego, J.M. Riveros, Theoretical calculation of pKa using the cluster continuum model, J. Phys. Chem. A, 106 (2002) 7434.
8. G.S. Schuurmann, M. Cossi, V. Barone, J. Tomasi, Prediction of the pKa of carboxylic acids using the ab initio continuum-solvation model PCM-UAHF, J. Phys. Chem. A, 102 (1998) 6706.

9. C.O. Silva, M.A. Silva, M.A.C. Nascimento, Ab initio calculations of absolute pKa values in aqueous solution I. carboxylic acids, J. Phys. Chem. A, 103 (1999) 11194.
10. A.M. Toth, M.D. Liptak, D.L. Phillips, G.C. Shields, Accurate relative pK calculations for carboxylic acids using complete basis set and Gaussian-n models combined with continuum solvation methods, J. Chem. Phys., 114 (2001) 4595.
11. M.J. Javan, Z. Jamshidi, Z. Aliakbar Tehrani, A. Fattahi, Interactions of coinage metal clusters with histidine and their effects on histidine acidity; theoretical investigation, Org. Biomol. Chem., 10 (2012) 9373.
12. G.A.A. Saracino, R. Improta, V. Barone, Absolute pKa determination for carboxylic acids using density functional theory and the polarizable continuum model, Chem. Phys. Lett., 373 (2003) 411.
13. J. Chen, M.A. McAllister, J.K. Lee, K.N. Houk, Short, strong hydrogen bonds in the gas phase and in solution: theoretical exploration of pKa matching and environmental effects on the strengths of hydrogen bonds and their potential roles in enzymatic catalysis, J. Org. Chem., 63 (1998) 4611.
14. K.R. Adam, New density functional and atoms in molecules method of computing relative pKa values in solution, J. Phys. Chem. A, 106 (2002) 11963.
15. A. Klamt, F. Eckert, M. Diedenhofen, M.E. Beck, First principles calculations of aqueous pKa values for organic and inorganic acids using COSMORS reveal an inconsistency in the slope of the pKa scale, J. Phys. Chem. A, 10 (2003) 9380.
16. R. Vianello, Z.B. Maksic, Strong acidity of some polycyclic aromatic compounds annulated to acyclopentadiene moiety and their cyano derivatives - A density functional B3LYP study, Eur. J. org. Chem., 16 (2005) 3571.
17. D.M. Chipman, Computation of pKa from dielectric continuum theory, J. Phys. Chem. A, 106 (2002) 7413.
18. G.I. Almerindo, D.W. Tondo, J.R. Pliego, Ionization of organic acids in dimethyl sulfoxide solution: a theoretical Ab initio calculation of the pKa using a new parametrization of the polarizable continuum model, J. Phys. Chem. A, 108 (2004) 166.
19. A.M. Magill, K.J. Cavell, B.F. Yates, Basicity of nucleophilic carbenes in aqueous and nonaqueous solvents theoretical predictions, J. Am. Chem. Soc., 126 (2004) 8717.
20. W.L. Jorgensen, J.M. Briggs, J. Gao, A priori calculations of pKa’s for organic compounds in water. The pKa of ethane, J. Am. Chem. Soc., 109 (1987) 6857.
21. F. Ding, J.M. Smith, H. Wang, First-principles calculation of pKa values for organic acids in nonaqueous solution, J. Org. Chem., 74 (2009) 2679.
22. C. Silva, E. Da Silva, M. Nascimento, Ab initio calculations of absolute pKa values in aqueous solution II. aliphatic alcohols, thiols, and halogenated carboxylic acids, J. Phys. Chem. A, 104 (2000) 2402.
23. M.D. Liptak, G.C. Shields, Accurate pKa calculations for carboxylic acids using complete basis set and gaussian-n models combined with CPCM continuum solvation methods, J. Am. Chem. Soc., 123 (2001) 7314.
24. S.E. Blanco, M.C. Almandoz, F.H. Ferretti, Determination of the overlapping pKa values of resorcinol using UV- visible spectroscopy and DFT methods, Spectrochim. Acta, Part A, 61 (2005) 93.
25. J. Klicic, R. Friesner, S.Y. Liu, W. Guida, Accurate prediction of acidity constants in aqueous solution via density functional theory and self-consistent reaction field methods, J. Phys. Chem. A, 106 (2002) 1327.
26. J. Pliego, J.M. Riveros, Theoretical calculation of pKa using the cluster continuum model, J. Phys. Chem. A, 106 (2002) 7434.
27. S. Zhang, J. Baker, P. Pulay, A reliable and efficient first principles-based method for predicting pKa Values. 1. Methodology, J. Phys. Chem. A, 114 (2010) 425.
28. C.P. Kelly, C.J. Cramer, D.G. Truhlar, Adding explicit solvent molecules to continuum solvent calculations for the calculation of aqueous acid dissociation constants, J. Phys. Chem. A, 110(7) (2006) 2493.
29. V.S. Bryantsev, M.S. Diallo, W.A. Goddard, pKa calculations of aliphatic amines, diamines, and aminoamides via density functional theory with a poisson boltzmann continuum solvent model, J. Phys. Chem. A, 11 (2007) 4422.
30. H. Lu, X. Chen, C.G. Zhan, First-principles calculation of pKa for cocaine, nicotine, neurotransmitters, and anilines in aqueous solution, J. Phys. Chem. B, 111 (2007) 10599.
31. Z. Jia, D. Du, Z. Zhou, A. Zhang, R. Hou, Accurate pKa determinations for some organic acids using an extended cluster method, Chem. Phys. Lett., 439 (2007) 374.
32. N. Sadlej-Sosnowska, Calculation of acidic dissociation constants in water: solvation free energy terms. Their accuracy and impact, Theor. Chem. Acc., 118 (2007) 281.
33. V. Verdolino, R. Cammi, B.H. Munk, H.B. Schlegel, Calculation of pKa values of nucleobases and the guanine oxidation products guanidinohydantoin and spiroiminodihydantoin using density functional theory and a polarizable continuum model, J. Phys. Chem. B, 112 (2008) 16860.
34. A. Trummal, A. Rummel, E. Lippmaa, P. Burk, I.A. Koppel, IEF-PCM calculations of absolute pKa for substituted phenols in dimethyl sulfoxide and acetonitrile solutions, J. Phys. Chem. A, 113 (2009) 6206.
35. R. Casasnovas, J. Frau, J. Ortega-Castro, A. Salva, J. Donoso, F. Munoz, Absolute and relative pKa calculations of mono and diprotic pyridines by quantum methods, J. Mol. Struct. (THEOCHEM), 912 (2009) 5.
36. F. Khalili, A. Henni, A.L.L. East, Entropy contributions in pKa computation: Application to alkanolamines and piperazines, J. Mol. Struct. (THEOCHEM), 916 (2009) 1.
37. J. Ho, M.L. Coote, pKa calculation of some biologically important carbon acids - an assessment of contemporary theoretical procedures, J. chem. Theory Comput., 5 (2009) 295.
38. J. Ho, M.L. Coote, A universal approach for continuum solvent pKa calculations: Are we there yet?, Theor. Chem. Acc., 125 (2010) 3.
39. F. Eckert, M. Diedenhofer, A. Klamt, Towards a first principles prediction of pKa: COSMO-RS and the cluster- continuum approach,Mol. Phys., 108 (2010) 229.
40. T. Simonson, J. Carlsson, D.A. Case, Proton binding to proteins: pKa calculations with explicit and implicit solvent models, J. Am. Chem. Soc., 126 (2004) 4167.
41. J. Mongan, D.A. Case, Biomolecular simulations at constant pH, Curr. Opin. Struct. Biol., 15 (2005) 157.
42. T.H. Click, G.A. Kaminski, Reproducing basic pKa values for turkey ovomucoid third domain using a polarizable force field, J. Phys. Chem. B, 113 (2009) 7844.
43. H. Li, A.W. Hains, J.E. Everts, A.D. Robertson, J.H. Jensen, The prediction of protein pKa’s using QM/MM: the pKa of lysine 55 in turkey ovomucoid third domain, J. Phys. Chem. B, 106 (2002) 3486.
44. D. Riccardi, P. Schaefer, Q. Cui, pKa calculations in solution and proteins with QM/MM free energy perturbation simulations: a quantitative test of QM/MM protocols, J. Phys. Chem. B, 109 (2005) 17715.
45. S.C.L. Kamerlin, M. Haranczyk, A. Warshel, Progress in Ab initio QM/MM free-energy simulations of electrostatic energies in proteins: accelerated QM/ MM studies of pKa, redox reactions and solvation free energies, J. Phys. Chem. B, 113 (2009) 1253.
46. J.E. Davies, N.L. Doltsinis, A.J. Kirby, C.D. Roussev, M. Sprik, Estimating pKa values for pentaoxyphosphoranes, J. Am. Chem. Soc., 124 (2002) 6594.
47. I. Ivanov, B. Chen, S. Raugei, M.L. Klien, Relative pKa values from first-principles molecular dynamics: the case of histidine deprotonation, J. Phys. Chem. B, 110 (2006) 6365.
48. C. Simo, G. Ciccotti, M.L. Klein, Computing the acidity of liquids via Ab initio molecular dynamics, Chem. Phys. Chem., 8 (2007) 2072.
49. Y. Fu, L. Liu, Y.M. Wang, J.N. Li, T.Q. Yu, Q.X. Guo, Quantum-chemical predictions of redox potentials of organic anions in dimethyl sulfoxide and reevaluation of bond dissociation enthalpies measured by the electrochemical methods, J. Phys. Chem. A, 110 (2006) 5874.
50. M. Sulpizi, M. Sprik, Acidity constants from vertical energy gaps: density functional theory based molecular dynamics implementation, Phys. Chem. Chem. Phys., 10 (2008) 5238. predictions of absolute pKa’s of organic acids in dimethyl sulfoxide solution, J. Am. Chem. Soc., 126 (2004) 814.
51. M. Sulpizi, M. Sprik, Acidity constants from DFT-based molecular dynamics simulations, J. Phys.: Condens. Matter., 22 (2010) 284116.
52. J. Cheng, M. Sprik, Acidity of the aqueous rutile TiO2(110) surface from density functional theory based molecular dynamics, J. Chem. Theory Compute, 6 (2010) 880.
53. M. Mangold, L. Rolland, F. Costanzo, M. Sprik, M. Sulpizi, J. Blumberger, Absolute pKa values and solvation structure of mmino acids from density functional based molecular dynamics simulation, Chem. Theory Comput., 7 (2011) 1951.
54. F. Kiani, A.A. Rostami, S. Sharifi, A. Bahadori, M.J. Chaichi, Determination of acidic dissociation constants of glycine, valine, phenylalanine, glycylvaline, and glycylphenylalanine in water using ab initio methods, J. Chem. Eng. Data, 55 (2010) 2732.
55. F. Kiani, A.A. Rostami, S. Sharifi, A. Bahadori, Calculation of acidic dissociation constants of glycylglycine in water at different temperatures using ab initio methods, Theochem., 956 (2010) 20.
56. A.D. Becke, Density‐functional thermochemistry. III. The role of exact exchange, J. Chem. Phys., 98 (1993) 5648.
57. C. Lee, W. Yang, R.G. Parr, Development of colle-salvetti correlation-energy formula into a functional of the electron density, Phys. Rev. B, 37 (1988) 785.
58. G.A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press: Oxford, 1997.
59. S. Sharifi, D. Nori-Shargh, A. Bahadori, Complexes of thallium(I) and cadmium(II) with dipeptides of L-phenylalanylglycine and glycyl-L-phenylalanine, J. Braz. Chem. Soc., 18 (2007) 1011.
60. N.C. Li, G.W. Miller, N. Solony, B.T. Gillis, The Effects of optical configuration of peptides: dissociation constants of the isomeric alanylalanines and leucyltyrosines and some of their metal complexes, J. Am. chem. Soc., 82 (1960) 3737.