User:J. C. Martinez-Garcia/Notebook/HMS Activities/2008/09/29

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The meeting

Today I went to the ([http://www.neurodiscovery.harvard.edu/symposium.html Annual Symposium: Protein Folding & Neurodegeneration]). It was a very interesting meeting, but I was very exhausted and because of that it was difficult to follow the talks at its deeper meaning. All the meeting was abou how misfolding of neuron proteins is at the origin of neuro-degenerative diseases. I think that the most interesting talk was th eone by Christopher M. Dobson (from Cambridge University, http://www.ch.cam.ac.uk/staff/cmd.html), who spoke about The Nature and Origins of Protein Misfolding Diseases. In fact he gave some argumnents on the evolutionary origin of this kind of diseases. See for instanxe the following paper: Dobson, Christopher M.1, Nature; 12/18/2003, Vol. 426 Issue 6968, p884-890 - Media:misfolding.pdf. This paper is in fact a very interesting one. I recovered some words from the text:

"However, it is apparent that biological systems have become robust not just by careful manipulation of the sequences of proteins but also by controlling, by means of molecular chaperones and degradation mechanisms, the particular state adopted by a given polypeptide chain at a given time and under given conditions. This process can be thought of as being analogous to the way in which biology regulates and controls the various chemical transformations that take place in the cell by means of enzymes. And just as the aberrant behaviour of enzymes can cause metabolic disease, the aberrant behaviour of the chaperone and other machinery regulating polypeptide conformations can contribute to misfolding and aggregation diseases".

From this paper I learnt that the folding of a protein depends on the energy landscape, which is encoded in the amino-acid sequence (many proteins have been shwon to refold from denatured states in a test tube in the absence of environmental factors). An energy landscape is a surface which represents the energy of interaction of the atoms involved as a function of their positions. Folding is a process which implies that a protein goes from an initial-random coil state to the lowest-energy conformation (in a very short time).

It seems there that robustness is always associated to energy constraints. The chaperons works then minimizing the combinatory explosion (reducing the possible conformations), making the protein to enter to the hoe which leaves to the minimal energy configuration. The cahperons must be then a sort of energy consumption regulator. I think that it would be convenient to read in detail some of the following papers:

  • Understanding protein folding via free-energy surfaces from theory and experiments by A. R. Dinner et al (Trends Biochem. Sci, July 2000). Here is the paper: Media:dinner.pdf.
  • How does a protein fold? by Sali et al, Nature 369, pp. 248-251. Here is the paper: Media:sali.pdf

On hysteresis

I think that the application of the analogy between the experimentally observed hysteresis in the case of the Zstk-FOXO1`a relation and dynamical mechanical friction is striking. In particular, the inhibition of mTOR via rapamicyn as considered in terms of friction compensation (through dithering) desserves to be taken into account. This is the zip file containing my toughts about the question Media:histeria.zip. The two loops metaphor must be not forgotten. I will continue with this research later.


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