Conformational Dynamics in Risk and Resilience Alleles of Apolipoprotein E (APOE) for Alzheimer's Disease

Apolipoprotein E (APOE) has three common main isoforms and myriad rare variants, each conferring risk or resilience to Alzheimer’s disease (AD) to varying degrees. The structural consequence of these variants is as yet unknown; to date, the only complete structure is heavily modified in order to prevent formation of higher order multimers, complicating structural determination. Here, we used multiple long-timescale (15 microseconds each) simulations to assess the conformational heterogeneity of 6 different forms of APOE, each with 6 replicates and totals 540 microseconds. We find that all APOE isoforms have substantial conformational plasticity, based mainly around the interaction between the N- and C-terminal domains. Principal component analysis shows the key motions for each isoform vary substantially, ranging from 36.7% to 55.7% of motion for the first two principal components. Additionally, we constructed energy-based residue interaction networks using per-residue generalized born and surface area solvation (MM/GBSA) interaction energies, where we identified isoform specific shifts in domain-domain and helix-helix interactions as a result of the changes to the amino acid sequence by isoform. These findings could aid in determining the nature of functional differences between isoforms, and therefore their enhanced risk/resilience, in Alzheimer’s disease.