Hydroperoxidized lipid membranes and its interaction with human islet amyloid polypeptide

CARLOS MANUEL CARLEVARO; DANIEL BARRERA; ESPINOSA, YANIS R.; EUGENIO LLANOS

Congreso; Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020; 2020

Oxidation has profound impact on the chemical structure of phospholipid fatty acids 1. The oxidized lipids are strongly suspected of playing an essential role in pathologies linked to oxidative stress1 i.e., Parkinson?s, Alzheimer?s, and diabetes 2. During the pathogenesis of type 2 diabetes, human islet amyloid polypeptide (hIAPP or amylin) binds to the membrane surface, and the secondary structure of hIAPP is modified before self-aggregating into amyloid fibrils. The latter implicated in pancreatic β-cell death 3. Molecular modelling approaches have been developed for oxidized lipids in membranes 2; nevertheless, the relationship between oxidized lipids and the hIAPP self-aggregation remains unknown. To analyze the conditions and understand the mechanisms by which oxidized lipids could increase amyloid formation of hIAPP, we built three membrane models. Each membrane model was composed of a single lipid representing a membrane system: (model i) neutral [1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)], (model ii) oxidized [hydroperoxized 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC-OOH)], and (model iii)  ionized [1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine  (POPS)], additionally, hIAPP monomer and explicit water were added in all cases. The molecular dynamics of each model was run using the CHARMM force field4. Our preliminary results suggest that on POPC-OOH membranes (model ii), the hydroperoxide group diffuses away from the nonpolar bilayer phase towards the polar aqueous surface. In POPC-OOH membrane a decrease of membrane bilayer thickness. The hIAPP shows a higher affinity for POPS and POPC-OOH membranes (models ii and iii) than POPC membranes (model i). These membrane models provide an insight into the molecular bases of the membrane disruption involved in β-cell death, determining the role of the biological oxidation in the hIAPP self-aggregating process in diseases such as Diabetes type II.