Effect of protective mutation on structure and dynamics of APOE: a molecular dynamics simulation study

Abstract

Apolipoprotein E (APOE) plays a significant role in determining the risk of Alzheimer's disease (AD). Three mutations—APOE3–R136S, APOE3–V236E, and APOE4–R251G—have been reported to reduce the risk of AD. Unveiling the molecular mechanism behind this reduction could lay a foundation for developing therapeutics for AD. To shed light on this subject, we investigate the mutation-induced variation in structural and dynamic properties of APOE3–R136S, APOE3–V236E, and APOE4–R251G in explicit solvent using molecular dynamics simulations. The APOE2, APOE3, and APOE4 were used as the reference. The analysis unveiled that the three protective mutations may exert protection through different mechanisms. The R215G mutation makes the flexibility of APOE4 proteins more similar to that of APOE2 and APOE3. In addition, this mutation reduced the exposure area of the oligomerization region by 5–16%. Such a reduction could alleviate the aggregation tendencies of the APOE proteins with amyloid-forming peptides. On the other hand, the R136S and V236 mutations alter the exposure area of the hydrophobic amino acid residues in the lipidation region. Their protective mechanisms may be due to the alteration in the lipidation capability of the APOE3 protein.