Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

12-POS Board 12 STRUCTURAL BASIS OF EPHA1 AND EPHA2 HOMO-DIMERIZATION AND WHOLE RECEPTOR INTERACTIONS USING COARSE GRAINED MARTINI 3 SIMULATIONS Matthias Buck ; Amita Sahoo 1 ; 1 Case Western Reserve University, Physiology and Biophysics, Cleveland, OH, USA EphA1 and EphA2 are receptor tyrosine kinases which play a critical role in cellular growth, differentiation and cell motility. Transmembrane dimerization is a key regulatory step in the activity and signaling process of these receptors. However, the involvement of the transmembrane (TM), the immediate two extracellular Fibronectin III domains (FN1&2) and the juxtamembrane (JM) region in the dimerization process is not clearly defined [1]. Therefore, studying the structural mechanisms of EphA1 and EphA2 dimerization and membrane interactions will help us better understand the signaling of these receptors. Molecular dynamics simulations have become a powerful tool to study membrane proteins and their interactions. Here, we modeled the domains of the EphA1 and EphA2 receptors and studied their structural mechanism of activation by using the coarse-grain (CG) molecular dynamics simulations using the recently published Martini3 potential function [2]. We show that the FN, TM and JM domains all differ in their interactions and in their interactions with the membrane between EphA1 and A2. In case of EphA2 most structures are non-dimeric, whereas FN domain dimerization is more compatible with TM helix dimers in EphA1. The underlying differences in the primary sequence which are likely responsible for these observations are discussed. Finally, we have started simulations on the whole length EphA2 receptor of around 600,000 particles (compared to the 6,500,000 atoms required for all atom simulations) and we have been able to run simulations of dimers- tetramers to 4 μs. References: [1] Sahoo AR, Buck M. Structural and Functional Insights into the Transmembrane Domain Association of Eph Receptors. Int J Mol Sci. 2021;22(16):8593. [2] Sahoo, AR, et al. Predicting Transmembrane (TM) Domain Dimer Structures using Martini 3. BioRxiv doi: https://doi.org/10.1101/2021.09.10.459840

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