Dominant-negative effects in prion diseases: insights from molecular dynamics simulations on mouse prion protein chimeras

Abstract

Mutations in the prion protein (PrP) can cause spontaneous prion diseases in humans (Hu) and animals. In transgenic mice, mutations can determine the susceptibility to the infection of different prion strains. Some of these mutations also show a dominant-negative effect, thus halting the replication process by which wild type mouse (Mo) PrP is converted into Mo scrapie. Using all-atom molecular dynamics (MD) simulations, here we studied the structure of HuPrP, MoPrP, 10 Hu/MoPrP chimeras, and 1 Mo/sheepPrP chimera in explicit solvent. Overall, ∼2 μs of MD were collected. Our findings suggest that the interactions between α1 helix and N-terminal of α3 helix are critical in prion propagation, whereas the β2–α2 loop conformation plays a role in the dominant-negative effect.

An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:4.

Keywords:

• prion protein
• dominant-negative
• molecular dynamics

Acknowledgments

We acknowledge the Jülich-Aachen Research Alliance (JARA) for computing resources on the JARA-HPC supercomputers. We thank the HPC-Europa2 project for funding a collaborative research visit that led to the results in this work. The authors wish to thank Erica Sarnataro for English language editing of the manuscript. This work has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under Grant Agreement No. 222887 – the PRIORITY project – and from the Ministero dell'Istruzione, dell'Università e della Ricerca under the program PRIN 2008 Meccanismi Neurodegenerativi nelle Malattie da Prioni: Studi Conformazionali, Fisiopatologia della Proteina Prionica e Possibili Approcci Farmacologici.