Solvent Accessibility and Computer Modeling Analysis on the Native and the Mutants of Human Prion Protein

Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases result from abnormally folded isoform (PrPSc) of the cellular prion protein (PrPC). In order to investigate the molecular mechanisms of the conversion of PrPC into PrPSc, we calculated the solvent accessibility of amino acid residues in native HuPrP and its single amino acid residual mutants, such as M166V, S170N, E200K and R220K. We also modeled structural overlaps of native PrP and its mutants, analyzed their root mean squared (RMS) deviations. Results showed that the local conformation is intensely different between the native PrP and its mutants owing to the variation of M166V etc. The single amino acid residual mutant not only lead to great changes of the solvent accessible surface area (SASA) and positions of part residues, but also influence the distribution of the protein surface charges. These changes may adapt well to the local surroundings of the secondary interactions. We also conclude that there is some difference between PrP and normal globular protein, indicating that PrP can’t form a stable globular protein; it’s only a folding intermediate.