Computational model reveals how prions replicate

A new computational model has revealed the mechanism of replication in prions, potentially opening new avenues for drug development against prion diseases – an area of great need.

Prions are known to replicate in the absence of genetic material by recruiting normal cellular prion protein (PrPC) and forcing conformational change to the infectious form (PRPSC), thus triggering fatal brain damage and other progressive symptoms such as personality changes and mobility restrictions. Previously, the insoluble and aggregated nature of prions has hampered the use of high-resolution techniques such as x-ray crystallography or NMR.

In this study, carried out by researchers from the University of Trento (Italy), the team revised previous models of prion structure and proposed a novel architecture based on new experimental data.

The new model allowed the team to apply algorithms for the reliable prediction of protein conformational transitions to the prion replication mechanism. These algorithms were derived from mathematical models of theoretical physics and were adapted to allow the simulation of complex biomolecular processes, allowing a better understanding of replication in prions.

Author, Giovanni Spagnolli (University of Trento) commented: “Cross-disciplinarity has been the key. Without the contribution of the colleagues from physics we would have never been able to afford the kind of calculation required to simulate such complex systems. For the first time we reconstructed a physically plausible mechanism of prion replication, which now allow us to formulate new hypotheses and design new drug discovery schemes to tackle the neurodegenerative processes unleashed by these infectious agents.”

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