Human Prion Protein Conformational Changes Susceptibility: A Molecular Dynamics Simulation Study

Abstract

Prion proteins are related to the development of incurable and invariably fatal neurodegenerative diseases in humans and animals. The pathogenicity involves the conversion of the host-encoded-alpha rich isoform of prion protein, PrP C , into a misfolded beta-strand rich conformer, PrP Sc. Although it has already been described that many punctual mutations alter the stability of PrP C , making it more prone to adopt an abnormal misfolded structure, the majority of cases reported among general population are sporadic in wild-type organisms. Thus, in this work we studied the dynamics and stability profiles of wild-type human prion protein by Molecular Dynamics (MD) simulation at different solvent temperatures. This analysis brought out certain residues and segments of the prion protein as critical to conformational changes; these results are consistent with experimental reports showing that protein mutants in those positions are related to the development of disease.

Structural and dynamical mechanisms of a naturally occurring variant of the human prion protein in preventing prion conversion*

“…The high flexibilities of these two regions are consistent with previous atomistic and coarsegrained simulation studies on WT PrP. [60][61][62][63][64] It is noted that the RMSF values in our work are much higher than those reported in the previous all-atom simulation studies, probably due to the much longer simulation time in our work than previous studies (2 ns, [60] 10 ns, [61] 1.8 ns, [65] 80 ns, [62] 50 ns, [63] 100 ns [58,59] ). To the best of our knowledge, our work is the first microsecond-scale all-atom MD simulation study on prion protein.…”