Computational analysis of cholesterol:POPC bilayer interacting with α7 nAChR

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

Cordoba

Congreso; LI Reunion Anual Sociedad Argentina de Biofísica; 2023

Sociedad Argentina de Biofísica

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels composed offive transmembrane glycoprotein subunits organized pseudosymmetrically around acentral pore or channel. Subtle changes in the lipid environment of nAChRs are highlyrelevant to their activity, producing significant effects on human biology. Lipids in thevicinity of the receptor can be located in annular or non-annular sites, with non-annularsites being in close contact with the receptor and exhibiting a low replacement rate, whileannular sites are farther away and have a higher replacement rate. A receptor modelbased on a known structure (PDB: 7EKI) was inserted into a lipid bilayer composedentirely of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids to create thecontrol system, which lacks cholesterol molecules. Subsequently, systems with differentcholesterol:POPC ratios in the membrane were generated, thus modifying the lipidenvironment of the nAChR. Atomistic Molecular Dynamics simulations were performed forthese systems focusing on the cholesterol molecules surrounding the transmembranedomain (TMD) of homomeric α7 nAChR. Physicochemical properties of the membrane andthe receptor were analyzed and compared with the results obtained for the controlsystem. Furthermore, the mobility of cholesterol molecules in the membrane was studied,and also the residues involved in the interactions of these molecules with TMD.