Atomic Scale Molecular Dynamics Simulation of Glycine Receptor in a Mixed Lipid Bilayer

The inhibitory glycine receptor (GlyR), is a membrane protein which mediates fast synaptictransmission in the central nervous system. In response to neurotransmitter binding, the GlyRopens pore through the lipid membrane, in order to facilitate the passive movement of small ions,down their electrochemical gradient.GlyR, as other membrane proteins, spends its time surrounded by lipids. For a long time,researchers thought that lipids were just a backdrop for the real players, while recent studies haverevealed their important roles in regulating the structure, function, and dynamics of membraneproteins [1]. In the absence of detailed structural and biophysical/biochemical characterization ofprotein/lipid interactions, Molecular dynamics (MD) simulations are able to provide a key tool,for probing the interactions of lipids with membrane proteins.This study aims to unravel the mutual interactions of mixed DPPC (DipalmitoylPhosphatidylcholine)-DMPC (DimyristoylPhosphatidylcholine) bilayer, with the embeddedmembrane protein, GlyR. In this respect, atomistic MD simulations were conducted on the threefollowing distinct systems: 1) Pure DPPC bilayer with 128 lipids, 2) Mixed phospholipid bilayer(DPPC60% - DMPC40%) and 3) The mixed bilayer, having the GlyR, embedded in.These systems were simulated for 100 ns, using the Gromacs simulation package (4.5.5) [2],while the gromos53a6 forcefield and Berger lipid parameters, were employed respectively forthe simulation of protein and lipids.Several structural properties, such as Root mean square deviation (RMSD), Radius ofgyration (Rg), Radial distribution function (RDF), Deuterium order parameter (DOP), Area perlipid (APL) and Bilayer thickness, were analyzed to assess the mutual interactions of protein andlipid molecules. For example, inspecting DOP plots revealed that adding DMPC molecules to theDPPC bilayer, leads to a clear decrease in the order of DPPC acyl chains. This is due to theshorter length of DMPC hydrocarbon tails, which forces the DPPC molecules to bendthemselves, in order to maximize the favorable hydrophobic interactions of DPPC-DMPChydrocarbon chains.On the other hand, insertion of GlyR in the mixed bilayer, increases the order parametersignificantly, which is an indication of the positive hydrophobic mismatch. Higher bilayerthickness around the box center, where GlyR was inserted, confirms this conclusion.

Keywords:

Glycine receptor , Phospholipid Bilayer , Molecular Dynamics Simulation