Influence of cholesterol:POPC bilayer ratios on modulating alpha7 nAChR

VIETRI AGUSTÍN; OBIOL DIEGO; AMUNDARAIN MARÍA JULIA; ZAMARREÑO FERNANDO; ANTOLLINI SILVIA SUSANA; COSTABEL MARCELO DANIEL

Congreso; 47th Annual Meeting of the Brazilian Biophysical Society; 2023

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels composed of five transmembrane glycoprotein subunits organized pseudosymmetrically around a central pore or channel. These receptors can adopt three main conformational states, along with several intermediate states: a closed (C) or resting (R) state, an open (O) state following agonist binding, and a desensitized (D) state that occurs after continuous presence of the agonist. Subtle changes in the lipid environment of nAChRs are highly relevant to their activity, producing significant effects on human biology. Lipids in the vicinity of the receptor can be located in annular or non-annular sites, with non-annular sites being in close contact with the receptor and exhibiting a low replacement rate, while annular sites are farther away and have a higher replacement rate. Interactions between cholesterol molecules and homomeric α7 nAChR were studied in this work, focusing on the transmembrane domain (TMD) of the receptor and its relationship with the surrounding lipids. A receptor model based on a known structure (PDB: 7EKI) was inserted into a lipid bilayer composed entirely of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids to create the control system, which lacks cholesterol molecules. Subsequently, systems with different cholesterol:POPC ratios in the membrane were generated, thus modifying the lipid environment of the nAChR. Atomistic Molecular Dynamics simulations were performed for these systems and then physicochemical properties of the membrane and the receptor were analyzed and compared with the results obtained for the control system. Furthermore, the interactions between cholesterol molecules and TMD were studied, including the residues involved and the mobility of these molecules in the membrane.