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  • Title: Control of the pathogenic conformational change of the prion protein by an attractor of low order.
    Author: Havsteen BH.
    Journal: J Theor Biol; 2004 Nov 07; 231(1):39-48. PubMed ID: 15363928.
    Abstract:
    The molecular vibrations of the infectious part of the prion protein has been studied by the methods of nonlinear dynamics using NMR-data of the protein in solution to test a new hypothesis for the nature of the pathogenic isomerization. The result was that the conformational change accompanying the conversion of the physiological form (PrP(c)) to the pathological (PrP(Sc)) one displays the characteristic properties of an attractor of the dimension 2.7+/-0.2, whereas the dimensions of the C-terminal, potentially infectious half of the physiological and the pathological forms are 5.3+/-0.3 and 3.9+/-0.3, resp. A plot of the average RMS of the vibrations per atom of the amino acids along the peptide chain suggests a pivotal role of E(167) and D(196). The vibrations of these residues are strongly dampened by the pathogenic conformational change suggesting that the neutralization to the hydrophobic form facilitates the isomerisation. This observation lends credence to the hypothesis that the pathological conformational change is released by the charge neutralization of the abundant, basic side chains lining the cleft in PrP(c) by a pK-shift caused by a transient ion flux from an action potential or by an RNA ligand. The attractor ensures that only the two conformers PrP(c) and PrP(Sc)-monomer, which are switching the polyadenylation of mRNA for synaptic proteins on and off, prevail. Some xenogenic PrP(Sc) seem to have a tendency to polymerize irreversibly, which is likely to inhibit the translation, thus killing neurons. The autocorrelation function is dampened (long correlation length for the 3 cases), the Poincaré plot seems to show the cross-section of a dense attractor for PrP(Sc) and a loose one for PrP(c), the Lyapunov exponent is positive and the power spectrum is broad. The Hurst plots of PrP(Sc) and PcP(c) show monofractality. The attractor hypothesis offers a supplement, or an alternative, to the current, inconclusive ideas of the nature of the PrP isomerization. The identification of the control factors may permit the reversal of the fatal conformational change. The dynamic parameters were checked by the interpoint distance method of Judd and by an analysis of the Fourier-transformed data.
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