proton pumping in bacteriorhodopsin with qm/mm scc-dftb
DESCRIPTION
Proton pumping in bacteriorhodopsin with QM/MM SCC-DFTB. Nicoleta Bondar, 1 Marcus Elstner, 2 Stefan Fischer, 3 S ándor Suhai, 4 and Jeremy C. Smith 1. 1 Computational Molecular Biophysics, IWR, University of Heidelberg, Germany 2 University of Braunschweig, Germany - PowerPoint PPT PresentationTRANSCRIPT
Proton pumping in bacteriorhodopsin
with QM/MM SCC-DFTB
Nicoleta Bondar,1 Marcus Elstner,2 Stefan Fischer,3
Sándor Suhai,4 and Jeremy C. Smith1
1Computational Molecular Biophysics, IWR, University of Heidelberg, Germany2University of Braunschweig, Germany3Computational Biochemistry, IWR, University of Heidelberg4Molecular Biophysics Department, German Cancer Research Center, Germany
Acknowledgements
IWR, University of Heidelberg
Prof. Jeremy C. SmithDr. Stefan Fischer
German Cancer Research Center
Prof. Sándor Suhai
University of Braunschweig
Prof. Marcus Elstner
University of Bremen
Prof. Thomas Frauenheim
€: The German Cancer Research Center (DKFZ) Heidelberg The German Research Foundation (DFG)
Bacteriorhodopsin proton pumping
Short-distance proton transfer (3-4 Å) from retinal to aspartate on the extracellular side:
Long-distance proton transfer (~11 Å)from aspartate on the cytoplasmic side to the retinal:
Involves proton transfers between the retinal chromophore and aspartic residues
Extracellular side
Extracellular side
Computing reaction pathways for bacteriorhodopsin proton pumping
Retinal
Asp85Asp212
Thr89
w402
Lys216
Quantum Mechanical / Molecular MechanicalQM: SCC-DFTB, B3LYP/6-31G**MM: CHARMM
ns range10s range
10ms range
Accuracy of SCC-DFTB in describing bacteriorhodopsin proton transferMethod Retinal
energy(donor)
Acetate energy(acceptor)
Δ E (acetate-retinal)
AM1 222.9 333.5 108.6
PM3 215.5 331.1 115.6
SCC-DFTB (&) 254.7 365.7 111.0
SCC-DFTB 265.0 365.7 100.7
HF/4-31G 263.6 364.2 100.6
HF/6-31G* 255.0 366.7 111.7
HF/6-31G** 257.7 370.9 113.2
HF/6-311+G** 258.6 361.3 102.7
B3LYP/4-31G 271.7 362.4 90.7
B3LYP/6-31G* 265.0 364.9 99.9
B3LYP/6-31G** 267.2 368.2 101.0
B3LYP/6-311+G** 261.6 352.6 91.0
MP2/6-31G* 252.3 362.3 110.0
MP2/6-31G** 256.7 368.5 111.8
MP2/6-311G* 248.7 358.3 109.6
MP2/6-311G** 252.3 365.6 113.3
MP2/6-311+G** 250.2 354.5 104.3
Accuracy of SCC-DFTB in describing bacteriorhodopsin proton transferMethod Retinal
energy(donor)
Acetate energy(acceptor)
Δ E (acetate-retinal)
AM1 222.9 333.5 108.6
PM3 215.5 331.1 115.6
SCC-DFTB (&) 254.7 365.7 111.0
SCC-DFTB 265.0 365.7 100.7
HF/4-31G 263.6 364.2 100.6
HF/6-31G* 255.0 366.7 111.7
HF/6-31G** 257.7 370.9 113.2
HF/6-311+G** 258.6 361.3 102.7
B3LYP/4-31G 271.7 362.4 90.7
B3LYP/6-31G* 265.0 364.9 99.9
B3LYP/6-31G** 267.2 368.2 101.0
B3LYP/6-311+G** 261.6 352.6 91.0
MP2/6-31G* 252.3 362.3 110.0
MP2/6-31G** 256.7 368.5 111.8
MP2/6-311G* 248.7 358.3 109.6
MP2/6-311G** 252.3 365.6 113.3
MP2/6-311+G** 250.2 354.5 104.3
AM1, PM3, and the standard SCC-DFTB overestimate the acetate-retinal proton affinity.
Accuracy of SCC-DFTB in describing bacteriorhodopsin proton transferMethod Retinal
energyAcetate energy
Δ E (acetate-retinal)
AM1 222.9 333.5 108.6
PM3 215.5 331.1 115.6
SCC-DFTB (&) 254.7 365.7 111.0
SCC-DFTB 265.0 365.7 100.7
HF/4-31G 263.6 364.2 100.6
HF/6-31G* 255.0 366.7 111.7
HF/6-31G** 257.7 370.9 113.2
HF/6-311+G** 258.6 361.3 102.7
B3LYP/4-31G 271.7 362.4 90.7
B3LYP/6-31G* 265.0 364.9 99.9
B3LYP/6-31G** 267.2 368.2 101.0
B3LYP/6-311+G** 261.6 352.6 91.0
MP2/6-31G* 252.3 362.3 110.0
MP2/6-31G** 256.7 368.5 111.8
MP2/6-311G* 248.7 358.3 109.6
MP2/6-311G** 252.3 365.6 113.3
MP2/6-311+G** 250.2 354.5 104.3
Regardless of the basis set used, B3LYP overestimates the Schiff base proton affinity.
Accuracy of SCC-DFTB in describing bacteriorhodopsin proton transferMethod Retinal
energyAcetate energy
Δ E (acetate-retinal)
AM1 222.9 333.5 108.6
PM3 215.5 331.1 115.6
SCC-DFTB (&) 254.7 365.7 111.0
SCC-DFTB 265.0 365.7 100.7
HF/4-31G 263.6 364.2 100.6
HF/6-31G* 255.0 366.7 111.7
HF/6-31G** 257.7 370.9 113.2
HF/6-311+G** 258.6 361.3 102.7
B3LYP/4-31G 271.7 362.4 90.7
B3LYP/6-31G* 265.0 364.9 99.9
B3LYP/6-31G** 267.2 368.2 101.0
B3LYP/6-311+G** 261.6 352.6 91.0
MP2/6-31G* 252.3 362.3 110.0
MP2/6-31G** 256.7 368.5 111.8
MP2/6-311G* 248.7 358.3 109.6
MP2/6-311G** 252.3 365.6 113.3
MP2/6-311+G** 250.2 354.5 104.3
Effective error cancellation.
Accuracy of SCC-DFTB in describing bacteriorhodopsin proton transferMethod Retinal
energyAcetate energy
Δ E (acetate-retinal)
AM1 222.9 333.5 108.6
PM3 215.5 331.1 115.6
SCC-DFTB (&) 254.7 365.7 111.0
SCC-DFTB 265.0 365.7 100.7
HF/4-31G 263.6 364.2 100.6
HF/6-31G* 255.0 366.7 111.7
HF/6-31G** 257.7 370.9 113.2
HF/6-311+G** 258.6 361.3 102.7
B3LYP/4-31G 271.7 362.4 90.7
B3LYP/6-31G* 265.0 364.9 99.9
B3LYP/6-31G** 267.2 368.2 101.0
B3LYP/6-311+G** 261.6 352.6 91.0
MP2/6-31G* 252.3 362.3 110.0
MP2/6-31G** 256.7 368.5 111.8
MP2/6-311G* 248.7 358.3 109.6
MP2/6-311G** 252.3 365.6 113.3
MP2/6-311+G** 250.2 354.5 104.3
SCC-DFTB (SRP) agrees reasonably well with B3LYP/6-31G** and MP2/6-311+G** in describing the retinal-acetate relative deprotonation energy.
Accuracy of SCC-DFTB in describing bacteriorhodopsin proton transfer
SCC-DFTB/MM-optimizedB3LYP 6-31G**/MM-optimized
QM/MM-optimized structures
QM/MM proton transfer activation energies
B3LYP/6-31G** and SCC-DFTB values agree to within 2.1 kcal/mol (rms value).
Computing reaction pathways for bacteriorhodopsin proton pumping
Retinal
Asp85Asp212
Thr89
w402
Lys216
Reaction path calculations
ns range10s range
1ms range
Computing pathways for proton transfer
The difficulties of choosing the reaction coordinate
Energy discontinuities are
present in the coordinate-
driving reaction path.
d = d1 – d2
Normalized (protein) RMSD
Energy discontinuities
correspond to large RMSD
differences.
The jumps in the structure
hide high energy peaks.
R
P
S1
S2
Computing pathways for proton transfer
Fischer & Karplus, Chem Phys Lett 1992
All degrees of freedom in the protein, no driving constraints
Optimizes an initial guess of the path
Conjugate Peak Refinement
R
P
S1
S2
Computing pathways for proton transfer
Fischer & Karplus, Chem Phys Lett 1992
Explore by varying the initial path
All degrees of freedom in the protein, no driving constraints
Optimizes an initial guess of the path
Conjugate Peak Refinement
Computing pathways for proton transfer
Retinal
Thr89
Asp85 w402Asp212
Lys216
R
P
Normalized reaction coordinate
Conjugate Peak Refinement
Coordinatedriving
… many paths must be computed with different starting coordinates
Energetics of bacteriorhodopsin proton pumping
Proton-donor group points in the direction opposite to the net transfer
Proton-donor group points in the direction of the net transfer
Energetics of bacteriorhodopsin proton pumping
protonateddeprotonated
Bondar, Smith, Fischer, Photochem. Photobiol. Sci. 2006
protonateddeprotonated
deprotonated
retinal reprotonation
Energetics of bacteriorhodopsin proton pumpingBondar, Smith, Fischer, Photochem. Photobiol. Sci. 2006
K
protonateddeprotonated
deprotonated
retinal reprotonation
protonated
Formation of the proton-transfer reactant state
X
Energetics of bacteriorhodopsin proton pumpingBondar, Smith, Fischer, Photochem. Photobiol. Sci. 2006
Mechanism of the first proton transfer step
Direct: E# = 12.4 kcal/mol
Asp212,w402 path: E# = 11.5 kcal/molThr89 path: E# = 13.6 kcal/mol
Experimental enthalpy barrier: ~13 kcal/mol
(Ludman et al, Biophys J. 1998)
CP
EC
Bondar, Elstner, Suhai, Smith, Fischer. Structure 2004
CP
EC
CP
EC
Directionality in the early photocycle steps
5
Twisting of the retinal chain is tuned such that
- Enough energy is stored to drive the photocycle
- Thermal cis-trans isomerization is energetically unfavourable
cytoplasm
Bondar, Fischer, Suhai, Smith, JPCB 2005
19
TwistedbR state
TwistedK state
12
QM/MM K-state model
Energy storage 7 kcal/mol in retinal twist + 7kcal/mol in perturbation of
h-bonding interactions