Insights into structural properties of denatured human prion 121-230 at melting temperature studied by replica exchange molecular dynamics.

Misfolding and aggregation of the prion protein (PrP) is responsible for the development of fatal transmissible neurodegenerative diseases. PrP undergoes structural conversion from a natively folded state into a misfolded state, resulting in aggregated amyloid fibrils. Partial unfolding has been recognized as an essential step in fibrillation, especially at the middle point of unfolding. To study the possible aggregation-prone states, we characterized the structure of the C-terminal globular domain of human prion (huPrP) 121-230 near extended conformation at melting temperature by replica exchange molecular dynamics (REMD) simulation, as the REMD method is the most suited generalized-ensemble algorithm that performs random walk in energy space and promotes a system to escape from local energy traps. Our results revealed that denatured huPrP is partially folded with α-helical structure at melting temperature. The simulation results provide further insight into the unfolding of prion, which is essential in pathogenesis of prion diseases.