Extended Data Fig. 7: Local conformational fluctuations and secondary structure changes induced by the p.Ala1527Gly substitution in ABCA7 open and closed conformations.

a, Phi vs. Psi dihedral angle distribution of residue 1527 over simulation time in open and closed ABCA7 conformations. b, Overall Phi vs. Psi angle distributions of residue 1527 across the entire simulation, comparing open and closed conformations. c, Time-resolved secondary structure assignments for residues 1517–1537. Alpha-helical regions highlighted in red; other colours indicate distinct secondary structures. d, Fraction of alpha-helical content for residues 1517–1537 during simulations. A value of 1 indicates continuous alpha-helical structure throughout duration of the simulation. e, Structural alignment of closed-conformation ABCA7 (purple; PDB ID: 8EOP) with ABCA1 (cyan; PDB ID: 7TBW). Gly1527 (ABCA7) and corresponding residue Val1646 (ABCA1) indicated as spheres. f, Structural alignment of closed-conformation ABCA7 (purple; PDB ID: 8EOP) with ABCA4 (green; PDB ID: 7LKZ). Gly1527 (ABCA7) and corresponding residue Ile1671 (ABCA4) indicated as spheres. a,d: G1527 refers to the ABCA7 structure with the risk variant (as present in the reference structures; Supplementary Table 15); G1527A refers to the ABCA7 structure with the mutated Gly→Ala change made to the reference structure in PyMOL.