Catalytic Mechanism of Dihydrofolate Reductase Enzyme. A Combined Quantum-Mechanical/Molecular-Mechanical Characterization of the N5 Protonation Step

Journal of Physical Chemistry B

Volumn 107, Issue 50, 2003, Pages 14036-14041

  Ferrer, Silvia ^a   Silla, Estanislao ^a   Tuñón, Iñaki ^a   Martí, Sergio ^b   Moliner, Vicent ^b  

^a UNIVERSITY OF VALENCIA   (Spain)

^b UNIVERSITAT JAUME I   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ADDITION REACTIONS; CATALYSIS; CHEMICAL BONDS; COMPUTER SOFTWARE; ENTROPY; ESCHERICHIA COLI; FREE ENERGY; FREQUENCIES; MOLECULAR DYNAMICS; POSITIVE IONS; POTENTIAL ENERGY; PROTONS; QUANTUM THEORY; REDUCTION; SUBSTRATES; X RAY CRYSTALLOGRAPHY;

ENERGY STRUCTURES; MOLECULAR REACTIONS; PROTONATION STEPS;

ENZYME KINETICS;

EID: 0347567536     PISSN: 15206106     EISSN: None     Source Type: Journal    
DOI: 10.1021/jp0354898     Document Type: Article

References (42)

1. Blakley, R. L. Folates and Pterins; Wiley: New York, 1984.
2. Fierke, C. A.; Johnson, K. A.; Benkovic, S. J. Biochemistry 1987, 26, 4085.
3. Kraut, J.; Matthews, D. A. In Biological Macromolecules and Assemblies; Jurnak, F. A., McPherson, A., Eds.; Wiley: New York, 1987.
4. (a) Cummins, P. L.; Ramnarayan, K.; Singh, U. C.; Gready, J. E. J. Am. Chem. Soc. 1991, 113, 8247.
5. (b) Cummins, P. L.; Greatbanks, S. O.; Rendell, A. P.; Gready, J. E. J. Phys. Chem. B 2002, 106, 9934.
6. Howell, E. E.; Villafranca, J. E.; Warren, M. S.; Oatley, S. J.; Kraut, J. Science 1986, 231, 1123.
7. Cannon, W. R.; Garrison, B. J.; Benkovic, J. J. Am. Chem. Soc. 1997, 119, 2386.
8. Howell, E. E.; Warren, M. S.; Booth, C. L. J.; Villafranca, J. E.; Kraut, J. Biochemistry 1987, 26, 8591.
9. Morrison, J. F.; Stone, S. R. Biochemistry 1988, 27, 5499.
10. Uchimaru, T.; Tsuzuki, S.; Tanabe, K.; Benkovic, J.; Furukawa, K.; Taita, K. Biochem. Biophys. Res. Commun. 1989, 161, 64.
11. Bystroff, C.; Oatley, S. J.; Kraut, J. Biochemistry 1990, 29, 3263.
12. McTigue, M. A.; Davies, I., J. F.; Kaufman, B. T.; Kraut, J. Biochemistry 1992, 31, 7264.
13. Chen, Y.; Kraut, J.; Callender, R. Biophys. J. 1997, 72, 936.
14. Gready, J. E. Biochemistry 1985, 24, 4761.
15. Gready, J. E.; Cummins, P. L.; Wormell, P. Adv. Exptl. Med. Biol. 1993, 338, 487.
16. Ivery, M. T. G.; Gready, J. E. Biochemistry 1995, 34, 3724.
17. Jeong, S. S.; Gready, J. E. Biochemistry 1995, 34, 3734.
18. A good example of this kind of methodologies can be found in the following references: (a) Turner, A. J. Doctoral Thesis, University of Bath, 1997.
19. (b) Moliner, V.; Turner, A. J.; Williams, I. H. J. Chem. Soc. Chem. Comun. 1997, 1271.
20. (c) Turner, A. J.; Moliner, V.; Williams, I. H. J. Phys. Chem. Chem. Phys. 1999, 1, 1323.
21. Castillo, R.; Andres, J.; Moliner, V. J. Am. Chem. Soc. 1997, 119, 2386.
22. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. J. Comput. Chem. 1983, 4, 187.
23. Barnes, J. A.; Williams, I. H. J. Chem. Soc., Chem. Commun. 1996, 193.
24. Barnes, J. A.; Williams, I. H. Biochem. Soc. Trans. 1996, 24, 263.
25. Sawaya, M. R.; Kraut, J. Biochemistry 1997, 36, 586.
26. Jorgensen, W. L.; Chandrasekhar, J.; Madura, J.; Impey, R. W.; Klein, M. L. J. Chem. Phys. 1983, 79, 926.
27. Field, M. J.; Bash, P. A.; Karplus, M. J. Comput. Chem. 1990, 11, 700.
28. Foresman, J. B.; Frisch, A. E. Exploring Chemistry with Electronic Structure Methods; Gaussian, Inc.: Pittsburgh, PA, 1993.
29. Fukui, K. J. Phys. Chem. 1970, 74, 4161.
30. García-Viloca, M.; Alhambra, C.; Truhlar, D. G.; Gao, J. J. Chem. Phys. 2001, 114, 9953.
31. AMI gas-phase calculations of a model system (a molecule of acetic acid that mimics the Asp27, the 6-methyl-substituted pterin that represents the DHF and one water molecule) predict that the reaction is endothermic by about 28 kcal/mol.
32. Marí, S.; Andrés, J.; Moliner, V.; Silla, E.; Tuñón, I.; Bertrán, J. Chem. Eur. J. 2003, 9, 984-991.
33. Torres, R. A.; Schiott, B.; Bruice, T. C. J. Am. Chem. Soc. 1999, 121, 8164-8173.
34. Castillo, R.; Silla, E.; Tuñón, I. J. Am. Chem. Soc. 2002, 124, 1809.
35. Radkiewicz, J. L.; Brooks, C. L., III. J. Am. Chem. Soc. 2000, 122, 225-231.
36. (a) Agarwal, P. K.; Billeter, S. R.; Rajagopalan P. T. R.; Benkovic S. J.; Hammes-Schiffer S. PNAS 2002, 99, 2794-2799.
37. (b) Agarwal, P. K.; Billeter, S. R.; Hammes-Schiffer S. J. Phys. Chem. B 2002, 106, 3283-3293.
38. (c) Watney J. B.; Agarwal, P. K.; Hammes-Schiffer S. J. Am. Chem. Soc. 2003, 125, 3745-3750.
39. (d) Rod T. H.; Radkiewicz, J. L.; Brooks, C. L., III. Proc. Natl. Acad. Sci. 2003, 100, 6980.
40. Warshel, A. Computer Modelling of Chemical Reactions in Enzymes and Solutions; John Wiley: New York, 1991.
41. Moliner, V.; Andres, J.; Oliva, M.; Safont, V. S.; Tapia, O. Theor. Chem. Acc. 1999, 101, 228.
42. As pointed out by Alhambra and co-workers (Alhambra, C.; Wu, L.; Zhang, Z.; Gao, J. J. Am. Chem. Soc. 1998, 720, 3858) in the original implementation of the link-atom approach (see ref 24) electrostatic interactions between the link atom and the rest of the protein atoms were not included in the quantum calculation. This, however, introduces an imbalance in electrostatic interactions in the QM region due to the fact that molecular orbitals are delocalized and such a partition, which excludes some terms in the Fock matrix, results in an unrealistically large partial charges on link atoms and the atoms they are attached to. This deficiency, inherent in CHARMM link-atom treatment, has to be always kept in mind, and conclusions must be discussed with caution unless a correction is taken into account. In this work, because the quantum link atom charges are constant in all the states, no change in the polarization have been induced by the MM charges from R to P. This result means that a minimal artifact result is obtained by the presence of these virtual H atoms in the relative magnitudes, although the total charge on C6 can be polarized by the close presence of the negative charge in the link atom. Due to this reason, we have preferred to calculate and analyze the sum of the charges of the pyrazine ring, which renders a more realistic result. Furthermore, the Mulliken charge analysis approach has been shown to be highly basis set dependent. Nevertheless, considering the rest of the limitations related with the AM1/ TIP3P optimization method implemented in CHARMM, the electronic analysis derived from these calculations can be considered qualitatively acceptable.