You could try with molecular dynamics analysis

If a structural model of your particular prion conformation is available, you can use FoldX to evaluate the effects of mutations on the folded part of the prion.

http://foldx.crg.es/

In case your mutations are in an intrinsically disordered region of the prion, you can use IUPred (or any other disorder predictor) to evaluate the effect of an amino acid substitution.

http://iupred.enzim.hu/

Hi Maria,

In our lab we usually characterize amyloidogenic proteins by Deep UV Resonance Raman (DUVRR) Spectroscopy , Normal Raman, Tryptophan Fluorescence, Atomic Force microscopy, and some times CD. To evaluate how a mutation in the prion peptide affects its conformation I would suggest any of the methods mentioned above. There are  many benefits associated with Raman spectrocopy for amyloidogenic peptides. It doesn't matter if your sample is soluble or precipitates (prion peptide can form insoluble fibrils rich in beta sheets). If you would like to estimate the amount of secondary structure components Deep UV Resonance Raman could help. Atomic force microscopy can help to see changes in morphology.

I'm not sure on how you can study the effect in function of prion protein but you can certainly study  the toxicity of the different polymorphic species  in neuroblastoma cells and the MTT assay.

Not the best way, but microcalorimetry of structural unfolding during thermal ramping reflects at least relative stabilites of polymorphic species.