Abstract
The mechanism and potential energy surface for the Baeyer–Villiger oxidation of acetone with hydrogen peroxide catalyzed by a Ser105–Ala mutant of Candida antarctica Lipase B has been determined using ab initio and density functional theories. Initial substrate binding has been studied using an automated docking procedure and molecular dynamics simulations. Substrates were found to bind to the active site of the mutant. The activation energy for the first step of the reaction, the nucleophilic attack of hydrogen peroxide on the carbonyl carbon of hydrogen peroxide, was calculated to be 4.4 kcal mol−1 at the B3LYP/6-31+G* level. The second step, involving the migration of the alkyl group, was found to be the rate-determining step with a computed activation energy of 19.9 kcal mol−1 relative the reactant complex. Both steps were found to be lowered considerably in the reaction catalyzed by the mutated lipase, compared to the uncatalyzed reaction. The first step was lowered by 36.0 kcal mol−1 and the second step by 19.5 kcal mol−1. The second step of the reaction, the rearrangement step, has a high barrier of 27.7 kcal mol−1 relative to the Criegee intermediate. This could lead to an accumulation of the intermediate. It is not clear whether this result is an artifact of the computational procedure, or an indication that further mutations of the active site are required.
Figure Second TS (18TS) in the Baeyer–Villiger oxidation in a mutant of CALB. Distances in Å
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References
Uppenberg J, Ohrner N, Norin M, Hult K, Kleywegt GJ, Patkar S, Waagen V, Anthonsen T, Jones TA (1995) Biochemistry 34:16838–16851
Magnusson A, Hult K, Holmquist M (2001) J Am Chem Soc 123:4354–4355
Branneby C, Carlqvist P, Magnusson A, Hult K, Brinck T, Berglund P (2003) J Am Chem Soc 125:874–875
Plesnicar B (1983) In: Patai S (ed) The chemistry of peroxides. Wiley, Chichester, p 559 and references therein
Renz M, Meunier B (1999) Eur J Org Chem 4:737–750 and references therein
Emmons WD, Lucas GB (1955) J Am Chem Soc 77:2287–2288
McClure J, Williams PH (1962) J Org Chem 27:24–26
Walsh CT, Chen YCJ (1988) Angew Chem Int Ed Engl 27:333–343 and references therein
Roberts SM, Wan PWH (1998) J Mol Catal B 4:111–136 and references therein
Lemoult SC, Richardson PF, Roberts SM (1995) J Chem Soc Perkin Trans 1 2:89–91
Pchelka BK, Gelo-Pujic M, Guibé-Jampel EJ (1998) J Chem Soc Perkin Trans 1 17:2625–2627
Björkling F, Frykman H, Godtfredsen SE, Kirk O (1992) Tetrahedron 48:4587–4592
Carter P, Wells JA (1988) Nature 332:564–568
Stoute VA, Winnik MA, Csizmiadia IG (1974) J Am Chem Soc 96:6388–6393
Okuno Y (1997) Chem Eur J 3:212–218
Cardenas R, Cetina R, Lagunez-Otero J, Reyes L (1997) J Phys Chem A 101:192–200
Cardenas R, Cetina R, Lagunez-Otero J, Reyes L (2000) J Mol Struct (THEOCHEM) 497:211–225
Hawthorne MF, Emmons WD, McCallum KS (1958) J Am Chem Soc 80:6393–6398
Carlqvist P, Eklund R, Brinck T (2001) J Org Chem 66:1193–1199
Hu C-H, Brinck T, Hult K (1998) Int J Quantum Chem 69:89–103
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639–1662
Guex N, Peitsch MC (1997) Electrophoresis 18:2714–2723
Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, Profeta SJ, Weiner P (1984) J Am Chem Soc 106:765–784
Besler BH, Merz KM, Kollman PA (1990) J Comput Chem 11:431–439
Åqvist J, Medina C, Samuelsson J (1994) Protein Eng 7:385–391
Marelius J, Hanssson T, Åqvist J (1998) Int J Quantum Chem 69:77–88
Kollman PA (1993) Chem Rev 93:2395–2417
van Gunsteren WF, Berendsen HJC (1987) Groningen molecular simulation (GROMOS) library manual. Biomos, Groningen, The Netherlands
Marelius J, Kolmodin K, Feierberg I, Åqvist J (1998) J Mol Graph Model 16:213–225
Åqvist J, van Gunsteren WF, Leijonmarck M, Tapia O (1985) J Mol Biol 183:461–477
Becke AD (1993) J Chem Phys 98:5648–5652
Lee C, Yang W, Parr RG (1988) Phys Rev B 37:785–789
Martin JML, EL-Yazal J, Francois J-P (1995) Mol Phys 86:1437–1450
Bauschlicher Jr CW, Partridge H (1995) Chem Phys Lett 240:533–540
Frisch MJ, Trucks GW, Schlegel HB Scuseria GE, Robb MA, Cheeseman JR, Zakrzewski VG, Montgomery JA, Stratmann E, Burant JC, Dapprich S, Millam JM., Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Baboul AG, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Gonzalez C, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andres JL, Head-Gordon M, Replogle ES, Pople JA (1998) Gaussian 98, Rev A7. Gaussian, Pittsburgh Pa.
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This work was supported by computing resources by the Swedish National Allocations Committee (SNAC).
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Carlqvist, P., Eklund, R., Hult, K. et al. Rational design of a lipase to accommodate catalysis of Baeyer–Villiger oxidation with hydrogen peroxide. J Mol Model 9, 164–171 (2003). https://doi.org/10.1007/s00894-003-0128-y
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DOI: https://doi.org/10.1007/s00894-003-0128-y