Glycation-induced conformational disruption in Apolipoprotein E3 impairs lipid and heparin binding functions: a molecular dynamics approach

Apolipoprotein E3 (ApoE3) plays crucial role in binding with lipids, heparin and lipid receptors to initiate the essential signaling cascade responsible for lipid metabolism. To execute these roles, apoE3 requires unique conformational attributes, including the association of the N-terminal (NT) and C-terminal (CT) domains, stability, helical amphipathicity and specific inter-residue interactions within the heparin binding site. Glycation in ApoE3 impairs the inter domain (NT and CT) association, stability and alters the helical amphipathicity and residue interaction of heparin binding site. Glycation destabilizes ApoE3 by disrupting the helixC1 lock and LoopN1 tethering, which triggers conformation alteration in CT domain and inter domain (NT and CT) interface. Furthermore, it perturbs the residue interaction network pattern of NT domain and helical orientation of helix4 and helixC2, which leads to conformational changes in NT domain and inter-domain interface respectively. The separation of the NT and CT domains reduces the dipolar environment of the lipid binding region and changes the amphipathicity of the heparin binding helical segment and also changes the residue interaction pattern of K143 and K146, which are necessary features of heparin binding. Free energy landscape (FEL) analysis confirms multiple energetically favorable conformational states in glycated systems, with expanded gap region distances between NT and CT domains, indicating impaired lipid-binding ability. Centrality analysis of residue interaction networks further underscores glycation induced reorganization of structural hubs, particularly within helix 4. These findings provide detailed molecular insights into glycation-induced structural destabilization and functional impairment of ApoE3, contribute to lipid metabolism disorders in diabetic conditions.