|The VES Hypothesis
Proteins are the
machines of life, they drive essentially all the physical and chemical processes that go on
in living cells: they catalyze reactions, pass signals and provide
basic structure. Although
they are many orders of magnitude smaller than man-made machines, they can perform similar tasks, such as transporting molecules from one part
of a cell to another and acting
as motors. Diseases are caused by the
malfunction of one or more proteins;
In spite of their importance, basic questions about the way proteins perform their functions remain unanswered. For instance, being constituted by hundreds or thousands of atoms, how do they, most of the times, acquire a specific three dimensional structure (the so-called protein folding problem) ? And how do they go from one conformation to another, as they do while working ? A standard proposal is to assume that folding and conformational changes are driven by random fluctuations and that the native structure of proteins corresponds to the global minimum of their free energy [1,2]. But this proposal is not consistent with the multifunnel energy landscape of proteins . Indeed, very different conformations of the same protein can have very similar (free) energies, as is illustrated above. All these conformations are equally probable, according to equilibrium thermodynamics.
The main objective of my current research is to test a different hypothesis about the way proteins work according to which the first step in protein folding and function is the storing of energy in the form of vibrational excited states (VES), something I propose to designate as the VES hypothesis. The possibility that VES have a role in protein function was first proposed in 1973, by McClare, in the context of a ``crisis in bioenergetics'' . This idea was taken up by Davydov  who was interested in the conformational changes responsible for muscle contraction, where the trigger and the energy donating reaction is the hydrolysis of adenosinetriphosphate (ATP). Computer simulations by Scott and co-workers showed that, at low temperature, VES are localized and propagate along the protein backbone in the form of solitons  while at biological temperatures they are still localized but propagate in a stochastic manner .
In recent years, experimental support for the validity, in proteins, of the Davydov/Scott model, has also been accumulating. This includes the measurement of the lifetimes of amide I excitations in myoglobin  and in crystals of acetanilide  which are 1-2 orders of magnitude larger than first thought , as well as the verification of the features of the Davydov/Scott model in NH excitations . But, since seeing is believing click below for a demonstration of amide I propagation in a real alpha-helix. The backbone is shown in red and the position of the vibration is shown in green. The positions of the protein atoms come from a simulation at 300 K with AMBER and the positions of the amide I come from a quantum mechanical simulation on that background. VMD was used to make this animation.
To see the animation click here.
The VES hypothesis can solve some of the problems in present-day theories of protein folding , it provides other causes for the malformation of proteins associated with misfolding diseases like Alzheimer's and Huntington's , and it can explain why enzymes are able to enhance the rate of a reaction by several orders of magnitude. I.e., the VES hypothesis is particularly appealing because it can integrate many of the properties of proteins. It has been suggested that new principles are needed to understand the way proteins work  and the VES hypothesis is a good basis for the development of such new principles. The aim of my research is to test the VES hypothesis, in all its consequences. These include protein folding  and function, as mentioned above, as well as more concrete questions such as why glutamine and asparagine tend to destabilize protein structure  and why enzymes are so big.
 Anfinsen, C.B., "Principles that govern the folding of protein chains", Science 181: 223-230 (1973); Bryngelson, J. and Wolynes, P. "Spin glasses and the statistical mechanics of protein folding", Proc. Natl. Acad. Sci. USA 84: 7524-7528 (1987).
 Dill, K.A and Chan, H-S. "From levinthal to pathways to funnels", Nature Struct. Biol. 4: 10-19 (1997); Karplus, M. "The levinthal paradox: yesterday and today", Fold. Des. 2: S69-S75 (1997).
 Cruzeiro-Hansson, L. and Silva, P.A.S. "Protein folding: thermodynamic versus kinetic control", J. Biol. Phys.27: S6-S9 (2001); L. Cruzeiro, "Exploring proteins multi-funnel energy landscape'', arXiv:0712.2034v2; L. Cruzeiro, "Protein Folding", Chem. Modell. 7: 89-114 (2010).
 McClare, C.W.F.,"Resonance in bioenergetics", Ann. N.Y. Acad. Sci. 227: 74-97 (1974).
 Davydov, A.S., "Solitons in Molecular Systems", Kluwer Academic Publ., Dordrecht, 2nd edition (1991).
 Scott, A., "The Davydov soliton revisited", Phys. Rep. 217: 1--67 (1992).
 Cruzeiro-Hansson, L. and Takeno, S., "Davydov model: The quantum, quantum-classical, and full classical model", Phys. Rev. E 56: 894--906 (1997).
 Xie, A., Meer, L.V.D, Hoff, W., and Austin, R.H., "Long-lived amide I vibrational modes in myoglobin: Breathers in biology" Phys. Rev. Lett. 84: 5435-5438 (2000); Austin, R.H., Xie, A., van der Meer, L., Shinn, M. and Neil, G. "Self-trapped states in proteins?" J. Phys. Condens. Matter.15: 1-6 (2003).
 Edler, J. and Hamm, P., "Self-trapping of the amide I band in a peptide model crystal", J. Chem. Phys. 117: 2415-2424 (2002); Edler, J. and Hamm, P., "Femtosecond Study of Self-trapped vibrational excitons in crystalline acetanilide. Phys. Rev. Lett. 88: 067403, 1-4 (2002); Edler, J. and Hamm, P., "Two-dimensional vibrational spectroscopy of the amide I band of crystalline acetanilide: Fermi resonance, conformational substates, or vibrational self-trapping?"J. Chem. Phys. 119: 2709-2715 (2003). Edler, J. and Hamm, P., "Spectral response of crystalline acetanilide and N-methylacetamide: vibrational self-trapping in hydrogen-bonded crystals", Phys. Rev. B 69: 214301, 1-7 (2004).
 Edler, J., Pfister, R., Pouthier, V., Falvo, C. and Hamm, P. "Direct Observation of Self-trapped vibrational states in alpha-helices", Phys. Rev. Lett. 93, 106405, 1-4 (2004).
 L. Cruzeiro, "Protein Folding", Chem. Modell. 7: 89-114 (2010).
 L. Cruzeiro , "Why are proteins with Glutamine- and Asparagine-rich regions associated with protein misfolding diseases?'' J. Phys.: Condens. Matter 17: 7833-7844 (2005); L. Cruzeiro,"Protein's multi-funnel energy landscape and misfolding diseases'', J. Phys. Org. Chem. 21: 549-554 (2008).
 R.B. Laughlin,
R.B., Pines, D., Schmalian, J., Stojkovic,
B. P. and Wolynes,
P., "The middle way" Proc Natl. Acad. Sci. USA 97: 32-37
©2005 Leonor Cruzeiro, all rights reserved.