Membrane cholesterol effect on the 5‐HT_2A receptor: Insights into the lipid‐induced modulation of an antipsychotic drug target

Abstract

The serotonin 5-hydroxytryptamine 2A (5-HT ) receptor is a G-protein-coupled receptor (GPCR) relevant for the treatment of CNS disorders. In this regard, neuronal membrane composition in the brain plays a crucial role in the modulation of the receptor functioning. Since cholesterol is an essential component of neuronal membranes, we have studied its effect on the 5-HT receptor dynamics through all-atom MD simulations. We find that the presence of cholesterol in the membrane increases receptor conformational variability in most receptor segments. Importantly, detailed structural analysis indicates that conformational variability goes along with the destabilization of hydrogen bonding networks not only within the receptor but also between receptor and lipids. In addition to increased conformational variability, we also find receptor segments with reduced variability. Our analysis suggests that this increased stabilization is the result of stabilizing effects of tightly bound cholesterol molecules to the receptor surface. Our finding contributes to a better understanding of membrane-induced alterations of receptor dynamics and points to cholesterol-induced stabilizing and destabilizing effects on the conformational variability of GPCRs.

Ligand with Two Modes of Interaction with the Dopamine D2 Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism

“…Simulations were carried out similarly to previously published protocols 45 − 47 using the ACEMD simulation package. 48 Ligand parameters were assigned by ParamChem from the CGenFF force field.…”

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

“…In this respect, MD simulations have proven useful to complement static data and expand our knowledge of processes such as binding of small molecules or drugs to orthosteric or allosteric receptor sites. We can also determine how a biomolecular system will respond to perturbations such as mutations, post-translational modifications, and the composition of the cell membrane [ 15 , 16 ]. In addition, we can study the conformational rearrangements that occur during receptor (in)activation, determine metastable receptor states along the transition pathways or explore the interaction with intracellular coupling partners [ 17 , 18 ].…”

“…As integral membrane proteins, GPCRs communicate with the lipid environment, which contributes to the regulation of GPCR function and dynamics. Membrane phospholipids have been found to allosterically modulate the activity [ 35 , 36 , 37 , 38 ] and oligomerization [ 19 ] of GPCRs, while membrane cholesterol can regulate its stability, ligand-binding properties and function [ 16 , 39 , 40 , 41 ]. Still, the precise nature of lipid implication in GPCR modulation is unclear.…”

Allostery in G protein-coupled receptors investigated by molecular dynamics simulations

“…Yet, most MD simulations of GPCR-lipid interactions published to date use very simple, often coarsegrained, lipid compositions of the cell membrane, and very few investigate the effect of different lipid environments on the receptor allosteric behavior, perhaps due to the large computational resources required to address these types of questions as well as the questions regarding the reliability of their force-fields [30]. A recent unbiased all-atom MD-based investigation, however, looked into the effect of cholesterol embedded in the lipid bilayer on the serotonin 5-hydroxytryptamine 2A receptor (5-HT2A) [31]. Here, a correlation was found between the presence of cholesterol and the structural flexibility of the system.…”