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;
thus, understanding how proteins work is a problem not only relevant to
biology in general, but also of great interest for medicine, biotechnology
and drug discovery.
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
To see the animation click
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
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"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",
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
 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).
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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).
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alpha-helices", Phys. Rev. Lett. 93, 106405, 1-4 (2004).
Modell. 7: 89-114 (2010).
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are proteins with Glutamine- and Asparagine-rich regions associated with
protein misfolding diseases?'' J. Phys.: Condens. Matter 17: 7833-7844
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multi-funnel energy landscape and misfolding diseases'', J. Phys. Org.
Chem. 21: 549-554 (2008).
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©2005 Leonor Cruzeiro,
all rights reserved.