Prevalent Mutations of Human Prion Protein: A Molecular Modeling and Molecular Dynamics Study

Abstract

Point mutations in the human prion protein gene, leading to amino acid substitutions in the human prion protein contribute to conversion of PrPC to PrPSc and amyloid formation, resulting in prion diseases such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), and fatal familial insomnia. We have investigated impressions of prevalent mutations including Q217R, D202N, F198S, on the human prion protein and compared the mutant models with wild types. Structural analyses of models were performed with molecular modeling and molecular dynamics simulation methods. According to our results, frequently occurred mutations are observed in conserved and fully conserved sequences of human prion protein and the most fluctuation values occur in the Helix 1 around residues 144-152 and C-terminal end of the Helix 2. Our analysis of results obtained from MD simulation clearly shows that this long-range effect plays an important role in the conformational fluctuations in mutant structures of human prion protein. Results obtained from molecular modeling such as creation or elimination of some hydrogen bonds, increase or decrease of the accessible surface area and molecular surface, loss or accumulation of negative or positive charges on specific positions, and altering the polarity and pKa values, show that amino acid point mutations, though not urgently change the stability of PrP, might have some local impacts on the protein interactions which are required for oligomerization into fibrillar species.

Structural Effects of Multiple Pathogenic Mutations Suggest a Model for the Initiation of Misfolding of the Prion Protein

“…[34] Some computational studies carried out on either wt PrP or pathogenic mutant variants revealed increased structural dynamics in a1 because of the movement of a1a way from a2-a3. [35,36] The antibody ICSM 18, which is known to bind to both a1a nd parts of a3, [37] has one of the highest therapeutic potencies for PrP,p resumably because it locks PrP and prevents its subdomain separation. Molecules that stabilize the Cterminus of a2h ave also proved to be effective antiprion drugs, both ex vivo and in vivo, [38] and most likely act by inhibiting step 2o fP rP misfolding.H ence,t he current study indicates that the inhibition of either step 1orstep 2ofPrP misfolding by the use of chemical chaperones or drugs would have therapeutic value.…”

Molecular Mechanism of the Misfolding and Oligomerization of the Prion Protein: Current Understanding and Its Implications

“…114 Several computational studies have showed increased structural dynamics in the α1 region during the early stages of PrP misfolding. 115,116 Page 10 of 44 Biochemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 11 The loop between β2 and α2 is another region that has been suggested to be critical for the misfolding of PrP. 117 The conformation and rigidity of this loop appears to determine prion disease transmission and susceptibility of a species.…”

A Molecular History of the Amyloidoses

“…In human Creutzfeldt-Jakob disease, the substrate protein bears a profibrillogenic mutation. 99 It has been argued that additional molecules may be involved; however, to date, none has been definitively identified. Amyloidogenic mutations in lysozyme also create a fibrillogenic precursor molecule that does not require proteolytic cleavage to initiate fibril formation in vivo.…”