ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations
Fig 3
Representative structures of ApoE isoforms.
(A) ApoE3 representative structure (i.e., centroid of the most populated cluster) from clustering analysis of the protein conformations extracted from the free energy basin at T1 (~275 K, see Fig 2B). The same compact, native state of the N-terminal helices is observed in all three ApoE isoforms (see S2A–S2C Fig). At T3 (~340 K, ~338 K, and ~328 K for ApoE2, ApoE3 and ApoE4 respectively) the representative structure of the intermediate state for: (B) ApoE2 exhibits an expanded volume of the N-terminal domain due to an increase of the average inter-helical distances; (C) ApoE3 exhibits a pairing of N-terminal helix–1 and helix–4 which separate from helix–2 and helix–3; (D) ApoE4 exhibits a separation of helix–1 from the other three helices. Such conformation represents the identified isoform-specific misfolded intermediate state (inter-residue contacts shown in S6A Fig) The size of the most populated cluster is reported in each panel. For all structures, helix–1 (H1), helix–2 (H2), helix–3 (H3), and helix–4 (H4) are represented in purple, green, blue, and red, cartoon respectively. The rest of the protein is represented in grey cartoon. (The sequence numbers for helices is reported in S1 Fig).