modeling and simulation of biological macromolecules.
Head: Stefan Fischer
University of Heidelberg
Interdisciplinary Center for Scientific
Im Neuenheimer Feld 205, room 3.212
Secr.: +49 (6221) 5414.736
Fax.: +49 (6221) 5414.728
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.
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.
- 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.
Hydrolysis of ATP in myosin (movies for article in Biochemistry,
The power stroke of myosin.
Actin-fibril structure and contractile
- Mechanics of the recovery stroke (movies for article
in PNAS, vol.102).
- Coupling between ATPase-activation and
for article in Structure, vol. 15).
- Principal motions of the
for article in J.Mol.Biol., vol. 367).
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
The proton-pump bacteriorhodopsin
- Mechanism of the molecular valve (movies for article in Structure,
- Storage of the photo-energy (movies for
article in J. Biol. Chem., vol.284)
- The primary proton transfer (movies for article in Structure,
- Primary proton transfer via water-B (movies
for article in J. Phys. Chem. B, vol. 112)
- The thermal back-isomerization of retinal
article in J. Phys. Chem. B, vol.109).
- Water pathways across retinal in
for article in J. Membr. Biol., vol.239)
- Catalytic mechanism of enzymes.
- Protein foldase (FKBP trans-cis
- Myosin catalyzed hydrolysis of ATP (movies for article in
- Catalysis of DNA-cleavage by the EcoR5
restriction enzyme (movies
for article in Biochemistry, vol.48).
- Complex functional changes of protein
- 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
- Simple accounting of solvent screening
effects: NUCS. (abstract)
- Vibrational entropy and
Poisson-Boltzmann solvation corrections. (abstract)
- QM/MM treatment of the ligand/protein complex.
- Motion of ligands in proteins.
- Methotrexate flip in DHFR (has a movie).
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
- Folding trap by a salt-bridge in Staphylococcal
Nuclease (movies for
article in Proteins, vol.50).