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Identifying Control Architecture and Manipulating Unfolding Pathways for Globular Proteins

L.S. Yilmaz, M.C. Demirel, and A.R. Atilgan*

Polymer Research Center, TUBITAK Advanced Polymeric Materials Research Center, and School of Engineering
Bogazici University, Bebek 80815, Istanbul, Turkey

This is an abstract for a presentation given at the
Seventh Foresight Conference on Molecular Nanotechnology.
There will be a link from here to the full article when it is available on the web.


The equilibrium dynamics of proteins is satisfactorily described by simple analytical methods[1]. It is now known that the folded proteins may be viewed as mechanical manipulators[2]. To identify the control architecture and to orchestrate the unfolding pathway, we derived the following set of equations: i) the equilibrium equation of each residue, ii) the constitutive relation for each tertiary contact and iii) the compatibility equation between the fluctuation of a residue and fluctuations of its tertiary bonds. In this study, i) we demonstrate that cooperatively inserted intra-residual fluctuations modarate the positional motion of residues that are responsible for the biological activities of globular proteins; ii) we identify a control architecture that is composed of a sensory region and adaptively distributed actuating parts; iii) we construct a template that is a subset of the native structure containing the controller; iv) we show that the template is conserved within the families of evolved sequences; and v) we obtain the ensemble of the transition state, that exhibits a weakening in the hydrophobic core and complete loss of native interactions in the packing region.

Cytochromes c (mitochondrial c, chloroplast c6, and bacterial c2), which is a family of heme proteins that play a key role in cell respiration; barnase, which is a microbial ribonuclease catalyzing the cleavage of single-standed RNA,; and chymotrypsin inhibitor 2 are studied thoroughly as benchmarking cases. The results conform with experiments and molecular dynamics simulations[3]. This newly proposed approach is particularly promising for characterizing the unfolding dynamics and reconstructing the unfolding potential energy surfaces of large proteins. Our formulation can monitor unbinding processes of ligands to proteins and the results are associated nicely with micromanipulation through atomic force microscopy[4].

  1. Bahar, I., Atilgan, A.R., and Erman, B., Fold. & Des., 2, 173, 1997; Bahar, I., Atilgan A.R., Demirel, M.C., Erman, B., Phys. Rev. Lett., 80, 2733, 1998; Demirel, M. C., Atilgan A. R., Jernigan, R. L., Erman, B., and Bahar, I., Protein Sci., 7, 2522, 1998; Bahar, I., Erman, B., Jernigan, R. L., Atilgan, A. R., and Covell, D., J. Mol. Biol., 285, 1023, 1999.
  2. Drexler, K. E., Proc. Natl. Acad. Sci. USA, 78, 5275, 1981; Drexler, K. E., Trends Biotech. 17, 5, 1999.
  3. Ptitsyn, O. B., J. Mol. Biol., 278, 655, 1998; Yeh, S-R., Takahashi, S., Fan, B., and Rousseau, D.L., Nature Struc. Biol., 4, 51, 1997; Li, A. and Daggett, V., J. Mol. Biol., 275, 677, 1998; Axe, D.D., Foster, N.W., Fersht, A.R., Biochemistry, 37, 7157, 1998.
  4. Bensimon, D., Structure, 4, 885, 1996; Rief, M., Pascual, J., Saraste, M., and Gaub, H.E., J. Mol. Biol., 286, 553, 1999.

*Corresponding Address:
A.R. Atilgan
Polymer Research Center, TUBITAK Advanced Polymeric Materials Research Center, and School of Engineering
Bogazici University, Bebek 80815, Istanbul, Turkey
Phone: +90 212 263 1540/2002 ext; Fax: +90 212 257 5032
Email:; WebURL:


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