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molecular simulations: enzyme reactivity
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MSI, MScBIOINFO
2012
Molecular simulations of enzyme reactivityMixing all concepts together
Jordi Villà i Freixa
[email protected] // cbbl.imim.esPrograma de Recerca en Informàtica Biomèdica
Universitat Pompeu FabraBarcelona
Barcelona, January 2012
MSI, MScBIOINFO
2012
Outline
Enzymes
1 Table of contents
2 Enzymes accelerate biochemical reactionsKinetic dataEnzyme reactivityGround state destabilization or TS stabilization?Electrostatic stressDesolvationDynamical effects in enzyme reactivityNear attack conformationsQuantum effects are also negligible in generalCatalysis by preorganized environment
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Enzymes accelerate biochemical rate constants,but up to some extend
[Bruice, 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Enzymes accelerate biochemical rate constants,but up to some extend
[Bruice, 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Putting kinetic data into context
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Putting kinetic data into context
E + L EL EL‡
!g‡cage
!g‡cat
!g‡p
!g‡w
L + L' LL' (LL')‡
!Gbind
EL‡
EL
LL'
(LL')‡
L + L'
E + L
!G
figure 1
JPC, feature article
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
What models have been proposed so far?
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
What models have been proposed so far?
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
What models have been proposed so far?
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
What models have been proposed so far?
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Linear free energy relationships
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Linear free energy relationships
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Linear free energy relationships
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Even metaloenzymes do not just depend on theelectronic structure
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
QM/MM
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
The empirical valence bond method
C1H11 O1
C1H11
R
R'C5
C6N1
C2
C3C4
R
R'
O1L1
H6
H5
H2
L2L1 L2
benzyl alcoholatebenzaldehyde NADH NAD+
RS 2RS 2
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
The empirical valence bond method
C1H11 O1
C1H11
R
R'C5
C6N1
C2
C3C4
R
R'
O1L1
H6
H5
H2
L2L1 L2
benzyl alcoholatebenzaldehyde NADH NAD+
RS 2RS 2
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
The empirical valence bond method
E1, E2
C1H11 O1
C1H11
R
R'C5
C6N1
C2
C3C4
R
R'
O1L1
H6
H5
H2
L2L1 L2
benzyl alcoholatebenzaldehyde NADH NAD+
RS 2RS 2
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
The empirical valence bond method
E1, E2
C1H11 O1
C1H11
R
R'C5
C6N1
C2
C3C4
R
R'
O1L1
H6
H5
H2
L2L1 L2
benzyl alcoholatebenzaldehyde NADH NAD+
RS 2RS 2
∣∣∣∣ E1 − V H12H12 E2 − V
∣∣∣∣ = 0
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
The empirical valence bond method
E1, E2V1, V2
C1H11 O1
C1H11
R
R'C5
C6N1
C2
C3C4
R
R'
O1L1
H6
H5
H2
L2L1 L2
benzyl alcoholatebenzaldehyde NADH NAD+
RS 2RS 2
∣∣∣∣ E1 − V H12H12 E2 − V
∣∣∣∣ = 0
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
The EVB: an intensively used method forenzyme reactivity studies
[Warshel and Weiss, 1980, Åqvist and Warshel, 1993,Kim et al., 2000, Villà and Warshel, 2001, Luzhkov, 2001,Bjelic, 2007, Sonnenberg and Schlegel, 2007,Higashi and Truhlar, 2008, Vardi-Kilshtain et al., 2009]Markus relationship:
∆GTS =(∆G + λ)2
4λ
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
[Via et al., 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
[Glennon et al., 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Reactivity in the Ras/RasGAP system
[Glennon et al., 2000,Allin and Gerwert, 2001]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Electrostatics: YES, but.. stress??
[Warshel et al., 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Electrostatics: YES, but.. stress??
[Warshel et al., 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Electrostatics: YES, but.. stress??
[Warshel et al., 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Electrostatics: YES, but.. stress??
[Warshel et al., 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
or creating a non-polar environment?
[Warshel et al., 2000]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
What about dynamics?
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
What about dynamics?
0 10 20 30 40 50-300
-250
-200
-150
-100
0 10 20 30 40 50-200
-150
-100
-50
0
NADH/B
NAD+/BH-
water
protein
Electrostatic fluctuations in LADH
εneutral
εion pair
εion pair
εneutral
O
H
H
N
CONH2
HZn
2+
NAD+BH-
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
What about dynamics?
-80 -60 -40 -20 0 20 40 60 80-300
-250
-200
-150
-100
-50
0
50
100
150
200
-80 -60 -40 -20 0 20 40 60 80-300
-250
-200
-150
-100
-50
0
50
100
150
200
Solvent coordinate !"elec / kcal/mol
Solvent coordinate !"elec / kcal/mol
Sol
ute
coor
dina
te !
" int /
kca
l/mol
Sol
ute
coor
dina
te !
" int /
kca
l/mol
water
protein
a)
b)
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Right, but perhaps the substrate is positioned torestrict its motions in a smart way...
[Shurki et al., 2002]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Right, but perhaps the substrate is positioned torestrict its motions in a smart way...
[Shurki et al., 2002]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Right, but perhaps the substrate is positioned torestrict its motions in a smart way...
[Shurki et al., 2002]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Contributions to the NAC effect
[Shurki et al., 2002]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Quantum effects in enzyme reactivity
Uq =P∑
k=1
12P
MΩ2∆x2k +
1P
U(xk )
C1H11 O1
C1H11
R
R'C5
C6N1
C2
C3C4
R
R'
O1L1
H6
H5
H2
L2L1 L2
benzyl alcoholatebenzaldehyde NADH NAD+
RS 2RS 2
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Quantum effects in enzyme reactivity
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Quantum effects in enzyme reactivity
0 5 10 15 20-2
-1.5
-1
-0.5
0!
!
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Quantum effects in enzyme reactivity
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
∆Gsol = ∆GQµ−∆Gµµ =
∆GQµ − 1
2∆GQµ = 12∆GQµ water
∆GQµ + 0 = ∆GQµ enzyme
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
[Barbany et al., 2003]
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Allin, C. and Gerwert, K. (2001).Ras catalyzes gtp hydrolysis by shifting negative charges from - to -phosphate as revealed bytime-resolved ftir difference spectroscopy.Biochemistry, 40(10):3037–3046.
Åqvist, J. and Warshel, A. (1993).Simulation of Enzyme Reactions Using Valence Bond Force Fields and Other Hybrid Quantum/ClassicalApproaches.93:2523–2544.
Barbany, M., Gutiérrez-de Terán, H., Sanz, F., Villà-Freixa, J., and Warshel, A. (2003).Pharmacophore approach for hapten design in catalytic antibodies generation.4:277–85.
Bjelic, S. (2007).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.
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Higashi, M. and Truhlar, D. (2008).Electrostatically embedded multiconfiguration molecular mechanics based on the combined densityfunctional and molecular mechanical method.Journal of Chemical Theory and Computation, 4(5):790–803.
Kim, Y., Corchado, J., Villa, J., Xing, J., and Truhlar, D. (2000).Multiconfiguration molecular mechanics algorithm for potential energy surfaces of chemical reactions.The Journal of Chemical Physics, 112:2718.
Luzhkov, V. B. (2001).Empirical valence bond study of radical reactions: hydrogen atom transfer in peroxidation of phenol.Chemical Physics Letters, 345(3-4):345 – 352.
Shurki, A., Štrajbl, M., Villà, J., and Warshel, A. (2002).How Much Enzymes Really Gain by Restraining Their Reacting Fragments?124:4097–4107.
Sonnenberg, J. and Schlegel, H. (2007).Empirical valence bond models for reactive potential energy surfaces. II. Intramolecular proton transfer inpyridone 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.
MSI, MScBIOINFO
2012
Outline
EnzymesKinetics
Enzymereactivity
GSD/TSS
Electrostaticstress
Desolvation
Dynamics
NAC
Quantum
Summary
Via, A., Ferre, F., Brannetti, B., Valencia, A., and Helmer-Citterich, M. (2000).Three-dimensional view of the surface motif associated with the p-loop structure: cis and trans cases ofconvergent evolution.303(4):455–65.455–65.
Villà, J. and Warshel, A. (2001).Energetics and Dynamics of Enzymatic Reactions.J. Phys. Chem. B, 105:7887–907.
Warshel, A., Štrajbl, M., Villà, J., and Florián, J. (2000).Remarkable Rate Enhancement of Orotidine 5’-monophosphate Decarboxylase is Due to Transition StateStabilization rather than to Ground State Destabilization.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.
