Molecular Dynamics Simulations Reveal Structural Changes Associated with the ABCA1 R230C Functional Variant.

The ATP-binding cassette transporter A1 (ABCA1) functional variant R230C (rs9282541) is associated with low plasma HDL-C levels, yet its atomic-scale mechanism remains unclear. We evaluated the structural and dynamic impact of R230C compared to wild-type (WT) ABCA1 using 200 ns molecular dynamics simulations in a lipid raft membrane. While the tertiary fold was preserved, R230C exhibited reduced overall flexibility (lower RMSD and localized RMSF rigidification) alongside a slightly expanded conformation (increased Rg and SASA). Localized fluctuations near residue 230 in extracellular domain 1 (ECD1) were coupled with decreased dynamic heterogeneity in distal functional regions, particularly nucleotide-binding domain 2 (NBD2) and transmembrane domain 2 (TMD2). MOSAICS analysis revealed subtle alterations in membrane thickness, midplane displacement, and lipid orientation. Furthermore, CAVER tunnel analysis demonstrated increased pathway heterogeneity (17 clusters in R230C vs. 10 in WT), lower persistence, and smaller bottleneck radii, disrupting the primary cholesterol transport route. Thus, R230C acts as a dynamic allosteric modulator and membrane-coupling agent rather than a folding-disruptive mutation, providing a biophysical rationale for reduced cholesterol efflux and low plasma HDL-C levels.