HGM2002 Poster Abstracts: 8. Disease Mechanisms
POSTER NO: 411
Interactions of PrP[106-126] with Prion, Scrapie, or Quinacrine In Silico
Pamela S.T. Ching, Whay K. Lau, Raymond M.W. Chau
PrP[106-126] is part of the prion protein that will change to beta-sheet conformation during the conversion of normal PrPC to PrPSc. It has been shown to be involved in neurotoxicity and peptide aggregation in prion diseases. Its trimer-channel formation is postulated to modulate Ca++ and Cu++ homeostasis that may lead to cytotoxicity. However, its interactions with PrPC, PrPSc, or drug (quinacrine) in silico have not been addressed. Using PDB files of PrP[106-126] docked against PrPC[1DWY], PrPSc[1B10], or quinacrine in GRAMM docking programme, we have studied  the molecular surface of the docks,  the atomic interactions between amino acids of the docks,  the docking energy and atomic distance relationship of the docks, in order to justify and understand the possibility of PrP[106-126] specifically interacting individually with PrPC, PrPSc, or quinacrine. The results of molecular surface revealed that due to the basic amino acids 106-111 and the hydrophobic amino acids 112-126 of PrP[106-126], both docked prion and scrapie globally changed from acidic to hydrophobic in general especially at the C-terminal. The 3D orientation of many residues of affected amino acids in prion and scrapie were altered. In the prion dock which exhibits the most stable interaction with docking energy -658, the basic region at +N-K110, S-M109, and HO-T107 of PrP[106-126] interact with the -O group of D167 and Q168, HO-S170, HO-Y226 of prion, respectively. In the scrapie dock which exhibits the most stable interaction with docking energy -840, the basic region at +N-H111, S-M109, S-M112, HO-T107, and NHCO-N108 of PrP[106-126] interact with the S-M129, HO-S132, -O-E221, HO-Y226, and -O-D227 of scrapie, respectively. In comparison, the basic region of PrP[106-126] reacts more focus at amino acids 167-170 and Y226 near the C-terminal of prion but reacts more diffusely with those amino acids spread out at 129, 132, 221, 226 and 227. Consequently, the binding of PrP[106-126] to scrapie has a higher chance of opening up the hairpin loop at residues 135-159 compared to prion. Quinacrine was used in treating prion disease patients with some success. We found through docking that it interacts with prion near Y225 and Y226 but with scrapie specifically at H140. In quinacrine dock with PrP[106-126] which exhibits the most stable interaction with docking energy -3881, quinacrine's N12 atom interacts with carbonyl-O of A117 and A118, C15 and C30 atoms with -CH3 of A117, C11 and C30 atoms with -CH3 of A118, and C17 and C22 atoms with -CH3 of V121 of PrP[106-126], respectively. Quinacrine preferentially interacts with the hydrophobic core (AGAAAAGAVV) which may prevent the formation of beta-sheet PrP[106-126] and the formation of aggregated fibril structures that causing neurotoxicity. The stable docking energy and the close distance between atoms of each docked molecule support the reliability of these studies.
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