Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

35-POS Board 35 DIFFERENCES IN CONFORMATIONAL ENSEMBLES OF HUMAN APOLIPOPROTEIN E ISOFORMS PROVIDE INSIGHT INTO ALZHEIMER'S DISEASE MECHANISMS Upasana L. Mallimadugula 1,3 ; Justin J Miller 1,3 ; Melissa D Stuchell-Brereton 1,3 ; Maxwell I Zimmerman 2 ; J. Jeremias Incicco 1,3 ; Debjit Roy 1,3 ; Louis Smith 1,3 ; Berevan Baban 1 ; Gregory T DeKoster 1 ; Carl Frieden 1 ; Andrea Soranno 1,3 ; Gregory R Bowman 1,3 ; 1 Washignton University in St. Louis, Biochemistry and Molecular Biophysics, St. Louis, MO, USA 2 Washington University in St. Louis, Pathology and Immunology, St. Louis, MO, USA 3 Washignton University in St. Louis, Center for Science and Engineering of Living Cells, St. Louis, MO, USA Alzheimer’s disease (AD) is a proteinopathy which results in severe cognitive impairment, loss of motor control, and death. Mutations in the APOE gene, which encodes the lipid transporting protein, apolipoprotein E (ApoE), are one of the strongest genetic risk factors for AD. ApoE occurs in three common isoforms ApoE2, ApoE3 and ApoE4, and homozygotes of ApoE4 have a 15-fold greater risk of developing the disease when compared to homozygotes of ApoE3. While the monomeric form of ApoE is proposed to be the disease relevant and lipid binding competent form, it is highly dynamic and prone to oligomerization at low concentrations. Together, these two facts have hindered traditional approaches towards obtaining structural data about the pathogenic forms of the protein. We hypothesized that the point mutations between the isoforms shift the conformational ensemble towards pathogenic conformations. Identifying such conformations would open up avenues for designing therapeutics that can shift the ensemble towards non-pathogenic conformations. We use the Folding@Home distributed computing network to perform Molecular Dynamics simulations of the isoforms in order to quantify the differences in their conformational ensembles. We combine our computational results with single molecule Forster Resonance Energy Transfer experiments performed on monomeric ApoE4 to understand the structural biology of this important class of proteins. We find that ApoE4 is considerably more dynamic than has been thought of based on previous structural data. We also identify allosteric effects between the regions of the polymorphisms between the isoforms and putative lipid-binding regions which could contribute to the differences in the pathogenicity of the isoforms.

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