Computational Structural Biology Research Unit

Biological complexes, structured ensembles of proteins or proteins/nucleic acids, perform many vital cellular functions, such as gene transcription, protein synthesis or regulation of cellular transport, and dysfunctions of those result in severe diseases. In order to understand diseases and develop treatments, the functional mechanisms of these biological complexes need to be elucidated. A crucial step in this process is the characterization of the structure and dynamics of these complexes.

As large complexes are difficult to study by X-ray crystallography, alternative low-resolution experimental techniques such as cryo-electron microscopy, small angle X-ray scattering and fluorescence resonance energy transfer are often used to characterize their conformational states. Additionally, new experimental developments of X-ray Free Electron Lasers (XFEL, such as in Spring 8, RIKEN) should provide structural information close to atomic resolution.

Our goal is to develop computational methods to obtain atomic level description of the functional states of biological complexes. Such methods will rely on the integration of various experimental data such as high resolution X-ray crystallography, lower resolution cryo-EM and emerging near atomic resolution XFEL through high performance computing such as with the K-computer. In addition, we aim to collaborate with experimental groups and the pharmaceutical industry to elucidate functional mechanism of biological systems.

Research Subjects

• Integration of computational tools with experimental data to build structural models of biological complexes
• Development of computational approaches to elucidate dynamics from experimental data
• Collaborative studies of biological systems with experimental groups and the pharmaceutical industry

Publications

1. Baker, J., Wright, S. H., and Tama, F.:
   "Simulations of substrate transport in the multidrug transporter EmrD"
   Proteins, 80, 1620-1632 (2012)
2. Ahmed, A., Whitford, P.C., Sanbonmatsu K.Y., and Tama, F.:
   "Consensus among flexible fitting approaches improves the interpretation of cryo-EM data"
   J. Struct. Biol., 177, 561-570 (2012)
3. Baumann, B.A.J., Taylor, D.W., Huang, Z., Tama, F., Fagnant, P.M., Trybus, K.M., and Taylor, K.:
   "Phosphorylated smooth muscle heavy meromyosin shows an open conformation linked to activation"
   J. Mol. Biol., 415, 274-287 (2012)
4. Miyashita, O., Gorba, C., and Tama, F.:
   "Structure Modeling from Small Angle X-ray Scattering Data with Elastic Network Normal Mode Analysis"
   J. Struct. Biol., 173, 451-460 (2011)
5. Katayama, H., Wang, J., Tama, F., Chollet, L., Gogol, E., Collier, R., and Fisher, M.:
   "Three-Dimensional Structure of the Anthrax Toxin Pore Inserted into Lipid Nanodiscs and Lipid Vesicles"
   PNAS, 107, 3453-3457 (2010)
6. Grubisic, I., Shokhirev, M.N., Orzechowski, M., Miyashita, O., and Tama, F.:
   "Biased coarse-grained molecular dynamics simulation approach for flexible fitting of X-ray structure into cryo electron microscopy maps"
   J. Struct. Biol., 169, 95-105 (2010)
7. Orzechowski, M., and Tama, F.:
   "Flexible fitting of high-resolution X-ray structures into cryo-electron microscopy maps using biased Molecular Dynamics simulations"
   Biophys. J., 95, 5692-5705 (2008)
8. Gorba, C., Miyashita, O., and Tama, F.:
   "Normal Mode Flexible Fitting of High-Resolution Structure of Biological Molecules toward 1 Dimensional Low-Resolution Data"
   Biophys. J., 94, 1589-1599 (2008)
9. Tama, F., Miyashita, O., and Brooks, C.L. 3rd.:
   "NMFF: Flexible high-resolution annotation of low-resolution experimental data from cryo-EM maps using normal mode analysis"
   J. Struct. Biol., 147, 315-326 (2004)