Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

36-POS Board 36 DIVERSE ROLES OF MEMBRANE IN FERROPTOTIC CELL DEATH. INSIGHTS FROM MOLECULAR DYNAMICS STUDY OF 15LOX1-PEBP1 COMPLEX Thiliban Manivarma 1,2 ; Karolina Mikulska-Ruminska 1,2 ; Wieslaw Nowak 1,2 ; 1 Nicolaus Copernicus University in Torun, Department of Biophysics, Torun, Poland 2 Centre for Modern Interdisciplinary Technologies, Torun, Poland Ferroptosis is recently discovered mechanism of cells death induced by unbalanced regulation one out of three major metabolic pathways involving iron, thiols or lipids, Ferroptosis is connected with such diseases as Alzheimer's disease, Parkinson's disease, sepsis, kidney injury, cancer etc. The process involves enzymatic and non-enzymatic means where the specific mechanisms are still unclear. The enzymatic form of ferroptosis involves iron dependent peroxidation of lipids performed by lipoxygenase (LOX). Presence of products (lipid peroxides) leads to the cell death. LOX is membrane-associated enzyme which imports lipids from the membrane. For the activity, a promiscuous Phosphatidylethanolamine Binding Protein 1 (PEBP1) is recruited. In a recent paper, 15LOX1-PEBP1 complex was modelled using coarse- grained approach in a simplified water environment (1). Here, we present extensive all-atoms molecular dynamics data on 15LOX1-PEBP1 system embedded in a realistic membrane environment. We repeat simulations for membrane-free complex and in that way we pinpoint structural differences in this system induced by interactions with membrane composed out of 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE) and 1-stearoyl-2-arachidonyl-phosphoethanolamine (SAPE). Moreover, we will discuss timescales involved in ferroptotic cell death and indicate metabolic steps requiring exa-scales computing power. Acknowledgment: Support of National Science Centre, Poland, No 2019/35/D/ST4/02203 (KMR, TM), is acknowledged. IDUB NCU #MEMOBIT grant (WN) and ICNT UMK computer facilities are acknowledged as well.1. Wenzel, S. E., et al. 2017. PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell. 171(3):628-641. e626.

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