Organisms have evolved a wide variety of mechanisms to utilize and respond to light. In many cases, the biological response is mediated by structural changes that follow photon absorption. These reactions typically occur at femto- to picosecond timescales, and are thus within reach of QM/MM molecular dynamics simulations.
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| AsFP, a switchable fluorescen t protein.. |
In our simulations, we use a multi-configurational quantum mechanical (QM) description (CASSCF, CASPT2) to model the electronic rearrangement for those parts of the system that are involved in the absorption. For the remainder, typically consisting of the apoprotein and the solvent, a simple forcefield model (MM) suffices.QM/MM gradients are computed on-the-fly, and a diabatic surface hopping procedure is used to model the excited state decay. We have demonstrated the validity of this hybrid QM/MM approach for photobiological reactions in recent applications on photoactivation of photoreceptor proteins, on photo-switching of fluorescent proteins and on benign and malign photochemical reactions in DNA. In addition to providing quantities that are experimentally accessible, such as structural intermediates, fluorescence lifetimes, quantum yields and spectra, the simulations provide also information that is much more difficult to measure experimentally, such as reaction mechanisms and the influence of individual aminoacid residues.
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| Potential energy surfaces on which photochemical reactions take place. |
In a new project, funded by the Volkswagen Foundation, we aim to go one step further and use computer simulation to design mutants with desired photochemical properties. This way we hope to contribute to new developments in for instance bio-imaging, and information technology.
Photoisomerization of the chromophore in the photoactive yellow protein, as observed in a molecular dynamics trajectory.
Electron transfer lies at the heart of biology. Despite the
availability of high-resolution x-ray structures of many of the
protein complexes involved in photosynthesis and metabolism, the
mechanistic details of how electron transfer occurs at a molecular
level are still unclear. Our current understanding of electron
transfer reactions is based on empirical models, such as Marcus
theory, which only provide a qualitative non-atomistic picture and
cannot be used to design new systems. To find out in atomistic detail
how proteins have evolved to meditate electron transfer processes and
how they reach the observed high efficiencies a more general
formulation of electron transfer is required.
Electron transfer is driven by geometrical distortions that change the
molecular orbitals. In biological systems these distortions are often
imposed by the protein environment. In addition, the response of the
environment upon changes in oxidation state of the prostetic groups
can have a strong dynamic effect as well.
Exposure to high doses of high-energy radiation causes irreversible damage in biological matter. At lower doses alteration of the genetic information is possible, leading to mutations. Despite the relevance of these processes in biology, little is known about the mechanism by which irradiation can cause destruction or mutation.
Using the multi-reference (CASSCF) electronic structure method to
compute the forces acting on the nuclei at each step of the molecular
dynamics simulation, the response of the system to the irradiation can
be studied in atomic detail.
Although we thus far addressed only
photochemical reactions initiated by optical transitions in
biomolecules, there are no restrictions on using our approach to
simulate also the effect of other radiation types on biomolecules,
including DNA and cell membranes.
Dimerization of two stacked thymine bases in a single DNA strand after absorption
of a UV photon.
In standard molecular dynamics simulations protons are assigned to titrating sites at the start of the simulation and not allowed to change. However, in proteins the protonation is intimately linked to conformation. Conformational changes can induce changes in protonation state, and vice versa. To take this correlations into account, we have developed a technique that treats protons as additional dynamic variables. Protons can be created and annihilated on-the-fly, depending on interactions with the local environment the and the pH. The latter is a parameter that users of the gromacs MD program can set. With this approach, we have a means to study the effect of pH on biomolecular processes, including catalysis (see below). Also, we have now a means to 'equilibrate' protons in x-ray structures, that do not show their positions.
The QM/MM method has become an established tool in computational
enzymatics. However, in most QM/MM studies, only the electrostatic
effect of the protein environment is considered. Dynamic contributions
are often overlooked. Protein motions can correlate strongly with the
reaction dynamics, suggesting why mutations far from the active site
can affect the catalysis.
Computing dynamic trajectories at room
temperature (300 K) is therefore more realistic than calculating the
minimum energy pathway (0 K), in which important entropic effects are
ignored. However, most enzymatic reactions are relatively slow
processes, ranging from microseconds to seconds, and are thus out of
reach for even the most efficient QM/MM sampling schemes available
today. In contrast, with the right choice of simulation protocol the
lower range of these time scales can be achieved in classical MD
simulations. Therefore, to explore the effect of the enzyme dynamics
on catalytic processes we combine long-term classical sampling
with occasional short QM/MM simulations.
Postdoctoral fellows
Phd students
Master students
Guests
Articles in peer-reviewed journals:
Book Chapters
QM/MM tutorials
Photosynthetic reaction cente
r embedded in a lipid bilayer.
DNA with a thymine dimer that
was formed after absorption of UV light.
Active site of Triosephosphate Isomeraze.
People
Principal Investigator
Publications
Light-induced structural changes in a photosynthetic reaction center caught by Laue diffraction.
Science, 328 (2010), 630-633.
Molecular basis of the light-driven switching of the photochromic fluorescent protein padron.
Journal of Biological Chemistry, 285 (2010), 14603-14609.
g membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation.
Journal of Computational Chemistry, 31 (2010), 2169-2174.
Computer Simulations of Photobiological Processes: the effect of the protein environment.
Advances in Quantum Chemistry, 59 (2010), 181-212.
Hydrogen bonding controls excited-state decay of the Photoactive Yellow Protein chromophore.
Journal of the American Chemical Society, 131 (2009), 13581-13581.
Inclusion of ionization states of ligands in affinity calculations.
Proteins: Structure, Function, and Bioinformatics, 76 (2009), 138-159.
Approximate switching algorithms for trajectory surface hopping.
Chemical Physics 351 (2008), 111-116.
Protein environment controls photoswitching of the asFP595 chromophore.
PLoS computational biology, 4 (2008), e1000034.
Arginine52 controls the photoisomerization process in photoactive yellow protein.
Journal of the American Chemical Society, 130 (2008), 3250-3251.
Ultra-fast deactivation channel for thymine dimerization.
Journal of the American Chemical Society, 129 (2007), 10996-10997.
Ultra-fast excited state decay of a cytosine-guanine basepair in DNA.
Journal of the American Chemical Society, 129 (2007), 6812-6819.
Photoswitching of the Fluorescent Protein asFP595: Mechanism, Proton Pathway, and Absorption Spectra.
Angewandte Chemie, Int. Ed. 119 (2007), 530-536.
The Planar Conformation of a Strained Proline Ring: a QM/MM Study.
Proteins: Structure, Function, and Bioinformatics, 64 (2006), 700-710.
Gromacs: Fast, Flexible and Free.
Journal of Computational Chemistry, 26 (2005): 1701-1718.
Photoactivation of the Photoactive Yellow Protein: Why photon absorption triggers a trans-to-cis isomerization of the chromophore in the protein.
Journal of the American Chemical Society, 126 (2004), 4228-4233.
Signal Transduction in the Photoactive Yellow Protein. II: Proton Transfer Initiates Conformational Changes.
Proteins: Structure, Function, and Genetics, 48 (2002), 212-223.
Signal Transduction in the Photoactive Yellow Protein. I: Photon Absorption and the Isomerization of the Chromophore.
Proteins: Structure, Function, and Genetics, 48 (2002), 202-211.
Excited state dynamics in biomolecules
In "Handbook of Molecular Biophysics"
Ed. H. Bohr, Wiley, New York (2009)
Conical Intersections and Photochemical Mechanisms: Characterizing the Conical Intersection Hyperline using Gradients, Second Derivatives, and Dynamics
In "Quantum Dynamics at Conical Intersections"
Ed. S. Althorpe and G. Worth, CPP6, Warrington (2004): 1-3.
QM/MM development
QM/MM webpage
Inserting membrane proteins
We have written a small program to insert a protein into equilibrated lipid bilayer systems. We hope it will be useful for your research.
pdf files von vorlesung un uebungen
files von vorlesung und practicals