Molecular dynamics simulation of local structural models of PrP^Screveals how codon 129 polymorphism affects propagation of PrP^Sc

Abstract

18Prions are unconventional pathogen without nucleotide genome and their pathogenic properties are defined by the primary 19 structure and the conformation of the constituent abnormal isoform (PrP Sc ) of prion protein (PrP). A polymorphic codon 129 of 20 human PrP that is valine (V129) or methionine (M129) is particularly influential on properties of PrP Sc , affecting transmission 21 efficiencies and clinicopathological features. However, how the single residue is so influential has not been elucidated because 22 the detailed structures of PrP Sc have not been determined yet due to its incompatibility with high-resolution structural analysis. 23 Previously we created an in-register parallel 42 are the influences of polymorphic codon 129 (in human numbering unless otherwise noted) of human PrP, which is either 43 methionine (M129) or valine (V129). Clinicopathological features of sporadic CJD vary depending on the polymorphism, in 44 terms of PrP deposition patterns and lesion profiles in the brain, and apparent molecular sizes of protease-resistant cores of 45 PrP Sc [5]. The PrP Sc from CJD patients homozygous for M129 tend to form diffuse tiny deposits in the brain with 21-kDa 46 protease-resistant core fragment. On the other hand, PrP Sc from CJD heterozygous or homozygous for V129 often forms

Molecular Dynamics and Machine Learning in Catalysts

“…Wide use of the AIMD approach, the computing speed and expenditure restricts the size of systems. As for the large systems, such as polymers [56,57], many active sites [58] and different approaches should be employed for simulation, like ReaxFF molecular dynamics. Unlike the AIMD approach, in which the electronic structure is solved directly, ReaxFF molecular dynamics is based on the reactive force field.…”