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Msi 0112 t3

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molecular simulations: enzyme reactivity

molecular simulations: enzyme reactivity

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  • 1. MSI, MScBIOINFO 2012 Molecular simulations of enzyme reactivity Mixing all concepts together Jordi Villà i Freixa jordi.villa@upf.edu // cbbl.imim.es Programa de Recerca en Informàtica Biomèdica Universitat Pompeu Fabra Barcelona Barcelona, January 2012
  • 2. MSI, MScBIOINFO 2012 1 Table of contentsOutlineEnzymes 2 Enzymes accelerate biochemical reactions Kinetic data Enzyme reactivity Ground state destabilization or TS stabilization? Electrostatic stress Desolvation Dynamical effects in enzyme reactivity Near attack conformations Quantum effects are also negligible in general Catalysis by preorganized environment
  • 3. Enzymes accelerate biochemical rate constants, but up to some extendMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Bruice, 2000]
  • 4. Enzymes accelerate biochemical rate constants, but up to some extendMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Bruice, 2000]
  • 5. Putting kinetic data into contextMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 6. JPC, feature article Putting kinetic data into contextMSI, MScBIOINFO 2012 (LL)‡ L + L LLOutlineEnzymesKineticsEnzyme (LL)‡reactivityGSD/TSS ∆g‡wElectrostaticstress ∆g‡cage ∆GDesolvation EL‡DynamicsNACQuantum LL L + L ∆g‡p ∆g‡catSummary E+L ∆Gbind EL E+L EL EL‡ figure 1
  • 7. What models have been proposed so far?MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 8. What models have been proposed so far?MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 9. What models have been proposed so far?MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 10. What models have been proposed so far?MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 11. Linear free energy relationshipsMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 12. Linear free energy relationshipsMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 13. Linear free energy relationshipsMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 14. Even metaloenzymes do not just depend on the electronic structureMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 15. QM/MMMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 16. The empirical valence bond methodMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzyme RS 2 RS 2reactivityGSD/TSSElectrostaticstress L1 L2 O1 L2Desolvation H11 O1 H11 L1Dynamics C1 H5 C4 R C1 RNAC C5 C3QuantumSummary C6 C2 H6 N1 H2 R R benzaldehyde NADH benzyl alcoholate NAD+
  • 17. The empirical valence bond methodMSI, MScBIOINFO 2012OutlineEnzymesKinetics RS 2 RS 2Enzymereactivity L1 L2 O1 L2GSD/TSS H11 O1 H11 L1 C1 H5 C4 R C1 RElectrostatic C5 C3stress C6 C2Desolvation H6 N1 H2Dynamics R RNACQuantum benzaldehyde NADH benzyl alcoholate NAD+Summary
  • 18. The empirical valence bond methodMSI, MScBIOINFO 2012 E1 , E2OutlineEnzymesKinetics RS 2 RS 2Enzymereactivity L1 L2 O1 L2GSD/TSS H11 O1 H11 L1 C1 H5 C4 R C1 RElectrostatic C5 C3stress C6 C2Desolvation H6 N1 H2Dynamics R RNACQuantum benzaldehyde NADH benzyl alcoholate NAD+Summary
  • 19. The empirical valence bond methodMSI, MScBIOINFO 2012 E1 , E2OutlineEnzymesKinetics RS 2 RS 2Enzymereactivity L1 L2 O1 L2GSD/TSS H11 O1 H11 L1 C1 H5 C4 R C1 RElectrostatic C5 C3stress C6 C2Desolvation H6 N1 H2Dynamics R RNACQuantum benzaldehyde NADH benzyl alcoholate NAD+Summary E1 − V H12 =0 H12 E2 − V
  • 20. The empirical valence bond methodMSI, MScBIOINFO 2012 E1 , E2 V1 , V2OutlineEnzymesKinetics RS 2 RS 2Enzymereactivity L1 L2 O1 L2GSD/TSS H11 O1 H11 L1 C1 H5 C4 R C1 RElectrostatic C5 C3stress C6 C2Desolvation H6 N1 H2Dynamics R RNACQuantum benzaldehyde NADH benzyl alcoholate NAD+Summary E1 − V H12 =0 H12 E2 − V
  • 21. The EVB: an intensively used method for enzyme reactivity studiesMSI, MScBIOINFO 2012Outline [Warshel and Weiss, 1980, Åqvist and Warshel, 1993,EnzymesKinetics Kim et al., 2000, Villà and Warshel, 2001, Luzhkov, 2001,Enzymereactivity Bjelic, 2007, Sonnenberg and Schlegel, 2007,GSD/TSSElectrostaticstress Higashi and Truhlar, 2008, Vardi-Kilshtain et al., 2009]DesolvationDynamics Markus relationship:NAC (∆G◦ + λ)2Quantum ∆GTS =Summary 4λ
  • 22. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 23. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 24. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Via et al., 200
  • 25. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 26. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 27. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 28. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 29. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Glennon et al., 2000]
  • 30. Reactivity in the Ras/RasGAP systemMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Glenno Allin and Gerwert, 2001]
  • 31. Electrostatics: YES, but.. stress??MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Warshel et al., 2000]
  • 32. Electrostatics: YES, but.. stress??MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Warshel et al., 2000]
  • 33. Electrostatics: YES, but.. stress??MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Warshel et al., 2000]
  • 34. Electrostatics: YES, but.. stress??MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Warshel et al., 2000]
  • 35. or creating a non-polar environment?MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Warshel et al., 2000]
  • 36. What about dynamics?MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 37. What about dynamics?MSI, MScBIOINFO 2012 Electrostatic fluctuations in LADH 2+Outline Zn O H H HEnzymes CONH 2 NADH/BKinetics BH-Enzyme N NAD+reactivityGSD/TSS 0Electrostaticstress -50 εneutralDesolvationDynamics -100NACQuantum -150 εion pairSummary water -200 0 10 20 30 40 50 -100 εneutral -150 -200 -250 εion pair protein -300 0 10 20 30 40 50 NAD+/BH-
  • 38. What about dynamics?MSI, MScBIOINFO a) 200 Solute coordinate ∆εint / kcal/mol 2012 150 100 50Outline 0 -50Enzymes -100Kinetics -150 waterEnzymereactivity -200GSD/TSS -250Electrostatic -300stress -80 -60 -40 -20 0 20 40 60 80Desolvation Solvent coordinate ∆εelec / kcal/molDynamics b) 200 Solute coordinate ∆εint / kcal/molNAC 150Quantum 100Summary 50 0 -50 -100 -150 protein -200 -250 -300 -80 -60 -40 -20 0 20 40 60 80 Solvent coordinate ∆εelec / kcal/mol
  • 39. Right, but perhaps the substrate is positioned to restrict its motions in a smart way...MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Shurki et al., 2002]
  • 40. Right, but perhaps the substrate is positioned to restrict its motions in a smart way...MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Shurki et al., 2002]
  • 41. Right, but perhaps the substrate is positioned to restrict its motions in a smart way...MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 42. Contributions to the NAC effectMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Shurki et al., 2002]
  • 43. Quantum effects in enzyme reactivityMSI, MScBIOINFO 2012Outline PEnzymes 1 1Kinetics Uq = MΩ2 ∆xk + U(xk ) 2Enzyme 2P Preactivity k =1GSD/TSSElectrostaticstress RS 2 RS 2DesolvationDynamicsNAC L1 L2 O1 L2Quantum H11 O1 H11 L1Summary C1 H5 C4 R C1 R C5 C3 C6 C2 H6 N1 H2 R R benzaldehyde NADH benzyl alcoholate NAD+
  • 44. Quantum effects in enzyme reactivityMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 45. Quantum effects in enzyme reactivityMSI, MScBIOINFO 2012OutlineEnzymes 0KineticsEnzymereactivityGSD/TSS -0.5ElectrostaticstressDesolvationDynamicsNAC -1Quantum ∆Summary -1.5 ∆ -2 0 5 10 15 20
  • 46. Quantum effects in enzyme reactivityMSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary
  • 47. MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantum ∆GQµ − 1 ∆GQµ = 2 ∆GQµ 1Summary 2 water ∆Gsol = ∆GQµ −∆Gµµ = ∆GQµ + 0 = ∆GQµ enzyme
  • 48. MSI, MScBIOINFO 2012OutlineEnzymesKineticsEnzymereactivityGSD/TSSElectrostaticstressDesolvationDynamicsNACQuantumSummary [Barbany et al., 2003]
  • 49. MSI, MScBIOINFO 2012 Allin, C. and Gerwert, K. (2001). Ras catalyzes gtp hydrolysis by shifting negative charges from - to -phosphate as revealed by time-resolved ftir difference spectroscopy.Outline Biochemistry, 40(10):3037–3046.Enzymes Åqvist, J. and Warshel, A. (1993).Kinetics Simulation of Enzyme Reactions Using Valence Bond Force Fields and Other Hybrid Quantum/ClassicalEnzyme Approaches.reactivity 93:2523–2544.GSD/TSSElectrostatic Barbany, M., Gutiérrez-de Terán, H., Sanz, F., Villà-Freixa, J., and Warshel, A. (2003).stressDesolvation Pharmacophore approach for hapten design in catalytic antibodies generation.Dynamics 4:277–85.NAC Bjelic, S. (2007).QuantumSummary Molecular Simulation of Enzyme Catalysis and Inhibition. Acta Universitatis Upsaliensis. Bruice, T. C. Benkovic, S. J. (2000). Chemical basis for enzyme catalysis. 39:6267–6274. Glennon, T. M., Villà, J., and Warshel, A. (2000). How Does GAP Catalyze the GTPase Reaction of Ras? A Computer Simulation Study. 39:9641–51.
  • 50. MSI, MScBIOINFO 2012 Higashi, M. and Truhlar, D. (2008). Electrostatically embedded multiconfiguration molecular mechanics based on the combined density functional and molecular mechanical method. Journal of Chemical Theory and Computation, 4(5):790–803.OutlineEnzymes Kim, Y., Corchado, J., Villa, J., Xing, J., and Truhlar, D. (2000).Kinetics Multiconfiguration molecular mechanics algorithm for potential energy surfaces of chemical reactions.Enzyme The Journal of Chemical Physics, 112:2718.reactivityGSD/TSS Luzhkov, V. B. (2001).Electrostatic Empirical valence bond study of radical reactions: hydrogen atom transfer in peroxidation of phenol.stress Chemical Physics Letters, 345(3-4):345 – 352.DesolvationDynamics Shurki, A., Štrajbl, M., Villà, J., and Warshel, A. (2002).NACQuantum How Much Enzymes Really Gain by Restraining Their Reacting Fragments?Summary 124:4097–4107. Sonnenberg, J. and Schlegel, H. (2007). Empirical valence bond models for reactive potential energy surfaces. II. Intramolecular proton transfer in pyridone and the Claisen reaction of allyl vinyl ether. Molecular Physics, 105(19):2719–2729. Vardi-Kilshtain, A., Roca, M., and Warshel, A. (2009). The empirical valence bond as an effective strategy for computer-aided enzyme design. Biotechnology journal, 4(4):495–500.
  • 51. MSI, MScBIOINFO 2012 Via, A., Ferre, F., Brannetti, B., Valencia, A., and Helmer-Citterich, M. (2000).Outline Three-dimensional view of the surface motif associated with the p-loop structure: cis and trans cases ofEnzymes convergent evolution.Kinetics 303(4):455–65.455–65.Enzymereactivity Villà, J. and Warshel, A. (2001).GSD/TSS Energetics and Dynamics of Enzymatic Reactions.Electrostaticstress J. Phys. Chem. B, 105:7887–907.DesolvationDynamics Warshel, A., Štrajbl, M., Villà, J., and Florián, J. (2000).NAC Remarkable Rate Enhancement of Orotidine 5’-monophosphate Decarboxylase is Due to Transition StateQuantum Stabilization rather than to Ground State Destabilization.Summary 39:14728–14738. Warshel, A. and Weiss, R. (1980). An empirical valence bond approach for comparing reactions in solutions and in enzymes. Journal of the American Chemical Society, 102(20):6218–6226.

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