Molecular dynamics simulations of early steps in RNA‐mediated conversion of prions

• Published in: Protein science Vol. 26; no. 8; pp. 1524 - 1534
• Main Authors: Alred, Erik J., Nguyen, Michael, Martin, Maggie, Hansmann, Ulrich H. E.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-08-2017; John Wiley and Sons Inc
• Subjects: Agglomeration; Aggregates; amyloid aggregation; Animal models; Animals; Binding Sites; Computer simulation; Humans; Mice; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Nucleic Acid Conformation; Poly A - chemistry; prion diseases; Prion protein; Prion Proteins - chemistry; Prions; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Folding; Protein Interaction Domains and Motifs; protein misfolding; Protein structure; Ribonucleic acid; RNA; RNA - chemistry; Secondary structure; Structural stability; Thermodynamics; prion diseases; amyloid aggregation; prions; RNA; protein misfolding
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.3178

The rate‐limiting step in prion diseases is the initial transition of a prion protein from its native form into a mis‐folded state in which the protein not only forms cell‐toxic aggregates but also becomes infectious. Recent experiments implicate polyadenosine RNA as a possible agent for generating the initial seed. In order to understand the mechanism of RNA‐mediated mis‐folding and aggregation of prions, we dock polyadenosine RNA to mouse and human prion models. Changes in stability and secondary structure of the prions upon binding to polyadenosine RNA are evaluated by comparing molecular dynamics simulations of these complexes with that of the unbound prions.