Misfolding dynamics of human prion protein.
We report the results of longest to date simulation on misfolding of monomeric human prion protein (HuPrP). By comparing our simulation of a partially unfolded protein to the simulation of the native protein, we observe that the native protein as well as native regions in the partially unfolded protein remain in the native state, and the unfolded regions fold back with increased extended (sheet and PP-II) conformations. The misfolded regions show increased basin hopping from non-helical basins while the amino acids locked in the helical conformation tend to stay locked in that conformation. Our results also validate the hypothesis that denaturation of helices and formation of a partially unfolded intermediate is required for misfolding as the native protein stayed in native conformation for the entire simulation. Finally, we also observe that there is no correlation between misfolding and the chemical identity of amino acids, as both hydrophobic and hydrophilic amino acids showed equal probability of sampling extensively from non-native conformations.
Zaman
Muhammad H
MH
Whitehead Institute and Division of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. mhzaman@mit.edu
D000596:Amino Acids / Q000737:chemistry; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D017433:Protein Structure, Secondary
D000596:Amino Acids; D011328:Prions