Chinese Physics B, Volume. 29, Issue 10, (2020)
Structural and dynamical mechanisms of a naturally occurring variant of the human prion protein in preventing prion conversion
Fig. 1. Stability and rigidity of WT PrP and its V127 variant. (a) A snapshot of the human PrP structure. (b)–(c) PDF of RMSD values in four consecutive time windows of (b) WT systems and (c) G127V systems. (d) RMSF of each residue on WT and G127V averaging over the three individual simulations for each system. The error bars are calculated by computing independent values from each individual simulation and taking the maximums and minimums of those values. The two regions where RMSF of G127V is remarkably lower than that of WT are labeled (1) and (2).
Fig. 2. Conformational characteristics of the S2–H2 loop. (a) Snapshots of the S2–H2 loop (residue 165–174) in three prion-resistant PrPs. The red and blue dashed boxes correspond to the two structural characteristics: a helix-like structure and a turn-like loop. (b) The Ramachandran plot of residue D167 in bank vole, elk, and horse PrPs. (c)–(f) Snapshots of the representative conformations of (c) the top four S2–H2 loop clusters in WT-1 MD run and of (c)–(e) the top one cluster in each G127V MD run. (g)–(h) PMF of D167 plotted as a function of the (
Fig. 3. Influence of G127V mutation on the interactions in the vicinity of residue 127 and S2–H2 loop. (a), (c), (f) Time evolution of (a) contact number between G/V127 and P165, (c) number of H-bonds between residues 125–129 and residues 162–169, and (f) centroid distance between residue R164 and D178 charged sidechain groups, in WT-1 (blue line) and in G127V-1 (red line). (b), (d), (g) Statistical analysis using a combined trajectory of the last 1.0 μs in the three simulations of WT and G127V systems. (e) Time evolution of H-bond numbers between residues 125–129 and residues 162–169. Only residue pairs forming H-bonds in more than 1/4 of simulation time are shown. (h)–(i) Representative snapshots of the N-terminal region and the S2–H2 loop region of (h) WT system, and (i) G127V system. (j)–(k) Snapshots of the G127V showing (j) the E168-involved H-bonds, and (k) the R164-D178 salt bridge.
Fig. 4. Allosteric paths from the mutation site (G/V127) to the C-terminal of H2 in WT and G127V systems. (a), (d) Optimal path from residue G/V127 to G195 in (a) WT PrP and (d) G127V. (b), (e) The correlation values of residue pairs forming the edges along (b) the G127–G195, and (e) the V127–G195 optimal paths. (c), (f) Percentage of optimal path length increase upon removal of each node of (c) WT and (f) G127V optimal paths.
Fig. 5. Correlation and community network analysis of WT and V127 variant. (a)–(b) Inter-residue correlation matrices of (a) WT and (b) G127V systems. (c)–(d) Community networks of (c) WT and (d) G127V systems. Left panels: snapshots of the proteins colored by communities. Right panels: schematic diagrams of the community networks. Each circle represents a single community. The size of the circle and the width of the edges correspond respectively to the size of the community and the connectivity strength between two communities.
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Yiming Tang, Yifei Yao, Guanghong Wei. Structural and dynamical mechanisms of a naturally occurring variant of the human prion protein in preventing prion conversion[J]. Chinese Physics B, 2020, 29(10):
Received: Jun. 24, 2020
Accepted: --
Published Online: Apr. 21, 2021
The Author Email: Wei Guanghong (ghwei@fudan.edu.cn)