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Computational Biochemistry
Group
Molecular
modeling and
simulation of biological macromolecules.
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Head: Dr.
Stefan Fischer
University of Heidelberg
IWR, Im Neuenheimer Feld 368, room 222
D-69120 Heidelberg
Germany
Secr.: +49 (6221) 54-8858
Fax.: +49 (6221) 54-8868
stefan.fischer@iwr.uni-heidelberg.de
Group
funding
Stefan
Fischer obtained his Ph.D. in biophysics from Harvard University in
1992, in the theoretical chemistry group of Martin Karplus (2013 Nobel
laureate), where he pioneered the development of computational methods
for studying complex motions and reactions in proteins. Since 1999, he heads the Computational
Biochemistry group at the Interdisciplinary Center for Scientific
Computing (IWR) of the University of Heidelberg.
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Research interests
Proteins are the little "machines"
that perform all the tasks in living systems. To understand in a
quantitative way how they function at the atomic level of detail, it is
necessary to use computer simulations, because there are no
experimental techniques that would allow to observe all the atoms of a
protein on the ultra-fast time-scale of their motion (which is on the
order of 10-14 seconds). Our main research focus has been
on protein nanomachines, such as molecular motors, trans-membrane pumps
and channels and catalytic enzymes.
Aside from using the now standard Molecular Dynamics
methods, we develop algorithms for finding reaction paths and
transition states in high-dimensional systems. This enables us to study
complex biomolecular processes that occur on time-scales beyond the
scope of standard molecular dynamics (i.e., slower than micro-seconds),
such as the motions of molecular motors in muscle. We also use combined
quantum/classical mechanics (QM/MM), which allow to accurately study
chemical reactions inside proteins, such as occurring in enzymatic
catalysis.
For all these different systems, we closely collaborate with
experimental research groups. The resulting knowledge serves to
optimize processes in biochemical engineering, to inspire developments
in the nanotechnologies, and to help pharma and biotechnological
research.
Research projects:
- Molecular motors.
- Structural mechanism of the Actin/Myosin motor during
muscle contraction:
- ATP-induced unbinding of myosin from actin, a.k.a. the rigor
dissociation step (movies for
article in PNAS,
vol.108).
- The recovery stroke of myosin.
- Mechanics
of the recovery stroke
(movies for
article in PNAS, vol.102).
- Coupling between ATPase-activation and recovery-stroke (movies for article
in Structure,
vol. 15).
- Principal motions of the recovery-stroke (movies for article
in J.Mol.Biol., vol. 367).
- Hydrolysis of ATP in myosin (movies
for article in Biochemistry, vol.45).
- The power stroke of myosin.
- Actin-fibril structure and contractile regulation.
- Structure, motion and flexibility of isolated Tropomyosin (movies for the
articles in J.Mol.Biol. vol. 395, and J.Struct.Biol.
vol.170).
- Light-driven trans-membrane pumps.
- The chloride-pump halorhodopsin
- Mechanism of the molecular valve (movies for article in Structure,
vol.13).
- Storage of the photo-energy (movies for
article in J. Biol.
Chem., vol.284)
- The proton-pump bacteriorhodopsin
:
- The primary proton transfer (movies
for article in Structure, vol.12).
- Primary proton transfer via water-B (movies
for article in J. Phys. Chem. B, vol. 112)
- The
thermal back-isomerization of retinal (movies
for article in J. Phys. Chem. B, vol.109).
- Water pathways across retinal in bacteriorhodopsin (movies for article
in J.
Membr. Biol., vol.239)
- Catalytic mechanism of enzymes.
- Protein foldase (FKBP
trans-cis proline isomerase).
- Myosin catalyzed
hydrolysis of ATP (movies
for article in Biochemistry, vol.45).
- Catalysis of DNA-cleavage by the EcoR5 restriction enzyme (movies for article
in Biochemistry, vol.48).
- Complex functional changes of
protein conformations.
- The signaling switch in the Ras
p21 GTPase (movies
for article in Proteins, vol.59).
- Cooperative transition in hemoglobin
upon oxygen binding (movies for
article in PNAS,
vol.108).
- Development of simulation methods.
- Fast methods for the prediction of ligand-binding affinities.
- Simple accounting of solvent screening effects: NUCS. (abstract)
- Vibrational entropy
and Poisson-Boltzmann solvation
corrections. (abstract)
- QM/MM treatment of the
ligand/protein complex. (full PDF)
- Motion of ligands in proteins.
- Methotrexate flip in DHFR
(has a
movie).
- Rotation of water in
ice
and BPTI
(has a movie).
- Sugar transport through the maltoporin
membrane-channel (movies for
article in Structure, vol.10).
- Folding and unfolding simulations of proteins.
- Folding trap by a salt-bridge in Staphylococcal Nuclease (movies for article in Proteins,
vol.50).
Former/Present
Students
Links: