title: Computation of kinetic isotope effects for enzymatic reactions.
abstract: We describe a computational approach, incorporating quantum mechanics into enzyme kinetics modeling with a special emphasis on computation of kinetic isotope effects. Two aspects are highlighted: (1) the potential energy surface is represented by a combined quantum mechanical and molecular mechanical (QM/MM) potential in which the bond forming and breaking processes are modeled by electronic structure theory, and (2) a free energy perturbation method in path integral simulation is used to determine both kinetic isotope effects (KIEs). In this approach, which is called the PI-FEP/UM method, a light (heavy) isotope is mutated into a heavy (light) counterpart in centroid path integral simulations. The method is illustrated in the study of primary and secondary KIEs in two enzyme systems. In the case of nitroalkane oxidase, the enzymatic reaction exhibits enhanced quantum tunneling over that of the uncatalyzed process in water. In the dopa delarboxylase reaction, there appears to be distinguishable primary carbon-13 and secondary deuterium KIEs when the internal proton tautomerism is in the N-protonated or in the O-protonated positions. These examples show that the incorporation of quantum mechanical effects in enzyme kinetics modeling offers an opportunity to accurately and reliably model the mechanisms and free energies of enzymatic reactions.
authors: Department of Chemistry and Supercomputer Institute, University of Minnesota, Minneapolis, MN 55455, US.
authors: Jiali
authors: J
authors: Gao
keywords: PI-FEP/UM; combined QM/MM; enzyme kinetics; kinetic isotope effects; path integral simulations
references: Nat Struct Biol. 2001 Nov;8(11):963-7
references: 11685243
references: Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20734-9
references: 19926855
references: Science. 1992 Oct 23;258(5082):631-5
references: 1411573
references: Chem Rev. 2006 Nov;106(11):4518-84
references: 17091928
references: J Am Chem Soc. 2005 Apr 20;127(15):5414-22
references: 15826179
references: Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 1995 Jul;52(1):178-188
references: 9963418
references: J Am Chem Soc. 2003 Sep 10;125(36):10877-84
references: 12952467
references: Chem Rev. 2006 Aug;106(8):3095-118
references: 16895320
references: J Am Chem Soc. 2011 Mar 30;133(12):4398-403
references: 21366322
references: Curr Opin Struct Biol. 2003 Apr;13(2):184-92
references: 12727511
references: Science. 2004 Jan 9;303(5655):186-95
references: 14716003
references: Chem Rev. 2006 Aug;106(8):3379-96
references: 16895333
references: Chem Rev. 2006 Aug;106(8):3140-69
references: 16895322
references: J Mol Graph Model. 2005 Oct;24(2):121-7
references: 15936231
references: Biochemistry. 1993 Jan 26;32(3):812-8
references: 8422386
references: Phys Rev Lett. 1987 Feb 9;58(6):563-566
references: 10034973
references: Chem Rev. 2006 Aug;106(8):3188-209
references: 16895324
references: J Am Chem Soc. 2005 Feb 23;127(7):2062-6
references: 15713081
references: Acc Chem Res. 2003 Aug;36(8):588-96
references: 12924955
references: J Chem Theory Comput. 2005 Sep;1(5):1008-16
references: 26641916
references: Curr Opin Chem Biol. 2009 Oct;13(4):475-83
references: 19640775
references: Biochemistry. 2006 Jan 31;45(4):1138-50
references: 16430210
references: J Phys Chem B. 2008 Mar 13;112(10):3149-56
references: 18271571
references: Phys Rev A Gen Phys. 1986 Dec;34(6):5080-5084
references: 9897894
references: J Comput Chem. 2008 Mar;29(4):514-22
references: 17722009
references: Annu Rev Phys Chem. 2002;53:467-505
references: 11972016
references: J Chem Theory Comput. 2006 Mar;2(2):236-45
references: 26626510
references: Nature. 2004 Sep 23;431(7007):396-7
references: 15385982
references: Acc Chem Res. 2002 Jun;35(6):341-9
references: 12069618
references: Angew Chem Int Ed Engl. 2009;48(7):1198-229
references: 19173328
references: J Chem Theory Comput. 2007 May;3(3):949-60
references: 26627415
references: Philos Trans R Soc Lond B Biol Sci. 2006 Aug 29;361(1472):1323-31
references: 16873120
references: Phys Rev B Condens Matter. 1985 Apr 1;31(7):4234-4244
references: 9936352
references: Biochemistry. 1999 Nov 23;38(47):15615-22
references: 10569946
references: Biochemistry. 2010 Jan 12;49(1):84-94
references: 19938875
references: Bioorg Chem. 2004 Oct;32(5):354-66
references: 15381401
references: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2017-22
references: 10681441
references: J Am Chem Soc. 2004 May 26;126(20):6244-5
references: 15149217
references: J Am Chem Soc. 2005 Nov 30;127(47):16374-5
references: 16305206
references: Arch Biochem Biophys. 2005 Jan 1;433(1):157-65
references: 15581574
references: Biochemistry. 1998 Oct 20;37(42):14943-7
references: 9778371
references: J Am Chem Soc. 2006 Dec 20;128(50):16345-57
references: 17165790
references: J Chem Theory Comput. 2009 Feb 17;5(3):459-467
references: 20490369