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A Kinetic Mechanism for Protein Folding

By: Leonor Cruzeiro
From: Univ. Algarve
At: Instituto de Investigação Interdisciplinar, B1-01
[2012-06-05] 11:30

According to the thermodynamics hypothesis [1] and the associated theory of a funnel-shaped free energy landscape [2-5], the native structure of proteins is that which minimizes its free energy. In this view, the protein folding problem is essentially solved [4,5] since finding a protein structure from its sequence, in a computer, depends solely on having a sufficiently accurate potential to describe the interactions of protein atoms with one another and on the availability of enough computer power to explore the protein conformational space. A question [6] that lurks underneath the funnel theory is whether the potential energy functions that are successful in the modelling of proteins and of their interaction with ligands do indeed lead to a funnel-shaped free energy landscape. In this talk, evidence for a multi-funnel landscape [7,8] is presented and a new, detailed, kinetic, mechanism for protein folding is put forward that can explain both reproducible folding in a multi-funnel free energy landscape, as well as the occasional misfolding [7,8]. Finally, the talk ends with a discussion of how this new kinetic mechanism fits with the existing experimental data on protein folding and misfolding.

[1] Anfinsen, C.B. (1973) Science 181, 223–230.

[2] Bryngelson, J.D., Onuchic, J.N., Socci N.D., and Wolynes, P.G. (1995) Proteins 21, 167-195.

[3] Dill, K.A. and Chan, H.-S. (1997) Nature Struct. Biol 4, 10-19.

[4] Wolynes, P.G. (2005) Quart. Revs. Biophys. 38, 405-410.

[5] Service, R.F. (2008) Science 321, 784-786.

[6] Cruzeiro-Hansson, L. and Silva, P.A.S. (2001) J. Biol. Phys. 27, S6-S9.

[7] Cruzeiro, L. (2008) J. Phys. Org. Chem. 21, 549-554.

[8] Cruzeiro, L. and Lopes, P.A. (2009) Mol. Phys. 107, 1485–1493.