Computational Biochemistry Group Molecular modeling and simulation of biological macromolecules.

Head:  Stefan Fischer

University of Heidelberg

Interdisciplinary Center for Scientific Computing (IWR)
Im Neuenheimer Feld 205, room 3.212
D-69120 Heidelberg
Germany

Secr.: +49 (6221) 5414.736
Fax.:  +49 (6221) 5414.728

 stefan.fischer@iwr.uni-heidelberg.de

Publications

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:

1. ATP-induced unbinding of myosin from actin, a.k.a. the rigor dissociation step (movies for article in PNAS, vol.108).
2. 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).
2. Hydrolysis of ATP in myosin  (movies for article in Biochemistry, vol.45).
3. The power stroke of myosin.
• Actin-fibril structure and contractile regulation.

3. 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
1. Mechanism of the molecular valve (movies for article in Structure, vol.13).
2. Storage of the photo-energy (movies for article in J. Biol. Chem., vol.284)
• The proton-pump bacteriorhodopsin :
1. The primary proton transfer (movies for article in Structure, vol.12).
2. Primary proton transfer via water-B (movies  for article in  J. Phys. Chem. B, vol. 112)
3. The thermal back-isomerization of retinal (movies for article in  J. Phys. Chem. B, vol.109).
4. 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.
• Molecular Kinematics of macromolecules.
• Algorithms for mapping out reaction paths:  CPR and Transition Networks
• Computing the free energy along reaction paths.
• Combined quantum/classical (QM/MM) calculations.

• 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).

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Publications

Former/Present Students

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Teaching

Masters/PhD/Postdoc positions

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Links:

• IWR
• Uni. Heidelberg