Molecular dynamic simulation of wild type and mutants of the polymorphic amyloid NNQNTF segments of elk prion: structural stability and thermodynamic of association.

A hexapeptide with amino acid sequence NNQNTF from the elk prion protein forms amyloid fibrils. Here we use molecular dynamic simulations of the oligomers and their single point glycine mutants to study their stability. In an effort to probe the structural stability and association thermodynamic in a realistic environment, all wildtype of NNQNTF polymorphic forms with different size and their corresponding double layer 5 strands single point glycine mutants were subjected to a total of 500 ns of explicit-solvent molecular dynamics (MD) simulation. Our results show that the structural stability of the NNQNTF oligomers increases with increasing the number of β-strands for double layers. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize the adjacent β-strands while the steric zipper is responsible for holding the neighboring β-sheet layers together. We used MM-PBSA approach free energy calculations to determine the role of nonpolar effects, electrostatics and entropy in binding. Nonpolar effects remained consistently more favorable in wild type and mutants reinforcing the importance of hydrophobic effects in protein-protein binding. While entropy systematically opposed binding in all cases, there was no observed trend in the entropy difference between wildtype and glycine mutant. Free energy decomposition shows residues situated at the interface were found to make favorable contributions to the peptide-peptide association. The study of the wild type and mutants in an explicit solvent may provide valuable insight for amyloid aggregation inhibitor design efforts.