Mammalian prion proteins (PrP) are of significant public health interest. Yeasts have proteins, which can undergo similar reconformation and aggregation processes to PrP, without posing a threat to the organism. These yeast "prions," such as SUP35, are simpler to experimentally study and model. Recent in vitro studies of the SUP35 protein found long aggregates, pure exponential growth of the misfolded form, and a lag time which depended weakly on the monomer concentration. To explain this data, we have extended a previous model of aggregation kinetics along with a stochastic approach. We assume reconformation only upon aggregation and include aggregate fissioning and an initial nucleation barrier. We find that for sufficiently small nucleation rates or seeding by a small number of preformed nuclei, the models achieve the requisite exponential growth, long aggregates, and a lag time which depends weakly on monomer concentration. The spread in aggregate sizes is well described by the Weibull distribution. All these properties point to the preeminent role of fissioning in the growth of misfolded proteins.

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We propose models for in vitro grown mammalian prion protein fibrils based upon left handed beta helices formed both from the N-terminal and C-terminal regions of the proteinase resistant infectious prion core. The C-terminal threading onto a b-helical structure is almost uniquely determined by fixing the cysteine disulfide bond on a helix corner. In comparison to known left handed helical peptides, the resulting model structures have similar stability attributes including relatively low root mean square deviations in all atom molecular dynamics, substantial side-chainto-side-chain hydrogen bonding, good volume packing fraction, and low hydrophilic/hydrophobic frustration. For the N-terminus, we propose a new threading of slightly more than two turns, which improves upon the above characteristics relative to existing three turn b-helical models. The N-terminal and C-terminal beta helices can be assembled into eight candidate models for the fibril repeat units, held together by large hinge (order 30 residues) domain swapping, with three amenable to fibril promoting domain swapping via a small (five residue) hinge on the N-terminal side. Small concentrations of the metastable C-terminal b helix in vivo might play a significant role in templating the infectious conformation and in enhancing conversion kinetics for inherited forms of the disease and explain resistance (for canines) involving hypothesized coupling to the methionine 129 sulfur known to play a role in human disease.

data. The reverse idea is used in the present paper: by comparing the two measured PSD curves, a shape factor is It is shown how a quantitative interpretation of the extracted, which is representative for the central size range well known diVerence of particle size measurements of the respective PSD curves. (sedimentation and low angle laser light scattering) can be used to yield information on particle shape. T hree kaolin types with diVerent granulometry and EXPERIMENTAL PROCEDURES composition were investigated. T he concept of a median Three types of Czech kaolin (all floated kaolins from shape factor is introduced and a simple approximative primary deposits) with rather different PSD curves and equation is given to calculate it from results of routine median sizes have been selected for the present investigation: size measurements. T his median shape factor may be Sedlec Ia (from the Karlovy Vary area), KDG, and KD50 advantageously used as an index for the routine charac-(both from the Podborany region). All these types are well terisation of powders with anisometric particles. For known and widely used in the ceramics industry. the kaolins investigated the value of the shape factor isThe suspensions have been prepared by mixing dry shown to correlate well with the content of (more kaolin powder with distilled water, adding deflocculant isometric) quartz grains. In contrast to the statistical (0•5-1•0 wt-%, based on solids, of a polyacrylic acid derivamethod of shape determination by optical image anative), and boiling under incessant stirring for 10 min. The lysis the ensemble method proposed here is less time final solids content of the suspensions is approx. 0•5 vol.-% consuming, does not require sophisticated sample prepin all cases. aration or specialised operators, and can be easilyThe sedimentation measurements were performed by the automated.BCT /449 classical Andreasen method with a fixed position pipette4 in a glass cylinder containing a column of suspension with T he authors are in the Department of Glass and initial height 200 mm. After certain times t constant sample Ceramics, Prague Institute of Chemical T echnology, volumes (10 mL) are removed from the suspension column T echnicka ´5, 166 28 Prague 6, Czech Republic at zero height (h=0), and the solid phase contained is (W

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