Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Poster Abstracts

13-POS Board 4 MODULATORY EFFECTS OF LIPID COMPOSITION ON THE CONFORMATIONAL DYNAMICS OF MGLUR2 IN VARIOUS FUNCTIONAL STATES: INSIGHTS FROM ALL-ATOM MOLECULAR DYNAMICS SIMULATIONS Ehsaneh Khodadadi 1 ; Shadi Badiee 1 ; Mortaza Derakhshani-Molayousefi 1 ; Ehsan khodadadi 1 ; Mahmoud Moradi 1 ; 1 university of Arkansas, Department of Chemistry and Biochemistry, Fayetteville, AR, USA Metabotropic glutamate receptor 2 (mGluR2) is a G protein-coupled receptor (GPCR) integral to regulating neurological functions and can be significantly affected by its surrounding lipid membrane environments. This study utilizes all-atom molecular dynamics simulations to explore the conformational dynamics of mGluR2 in both active and inactive states, contextualized by lipid interactions. Here, we embedded mGluR2 protein in various micelles using BLMNG detergent and lipid bilayers composed of palmitoyl-oleoyl phosphatidylcholine (POPC) and Cholesteryl hemisuccinate (CHS) and investigated conformational dynamics of mGluR2 across different CHS concentrations (0%, 10%, 25%) to understand the lipid's modulatory effects on receptor conformation. Our simulations have brought to light distinct conformational variations between the inactive and active mGluR2. In the inactive state, the receptor exhibited enhanced conformational flexibility, particularly within the transmembrane helices, which contrasts with the more stable conformation of its active state. CHS plays a significant role in these dynamics, especially at 10%, facilitating notable conformational changes in transmembrane domains. This result underscores the critical role of lipid composition in GPCR activity. We have uncovered substantial conformational rearrangements, particularly in the TM7 transmembrane domains, which play a significant role in the behavior of mGluR2. Furthermore, we have identified key electrostatic interactions that have significant contributions on the conformations of the inactive and active mGluR2, specifically influenced by TM7. These insights not only underscore the importance of the lipid environment in modulating GPCR structure and function but also provide a deeper understanding of the dynamic behavior of mGluR2. This understanding can be harnessed to develop targeted therapeutics for mGluRs and potentially other GPCRs by exploiting their lipid-dependent conformational states. This study significantly advances our understanding of receptor behavior in diverse lipid contexts, paving the way for innovative drug discovery and therapeutic optimizations targeting neurological and synaptic disorders.

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