Abstract
The human β2-adrenergic receptor (β2AR) belongs to the G protein-coupled receptor (GPCR) family and due to its central role in bronchodilation, is an important drug target. The inter-individual variability in β2AR has been implicated in disease susceptibility and differential drug response. In this work, we identified nine potentially deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) using a consensus approach. The deleterious nsSNPs were found to cluster near the ligand binding site and towards the G-protein binding site. To assess their molecular level effects, we built structural models of these receptors and performed atomistic molecular dynamics simulations. Most notably, in the Phe290Ser variant we observed the rotameric flip of Trp2866.48, a putative activation switch that has not been reported in β2AR thus far. In contrast, the variant Met82Lys was found to be the most detrimental to epinephrine binding. Additionally, a few of the nsSNPs were seen to cause perturbations to the lipid bilayer, while a few lead to differences at the G-protein coupling site. We are thus able to classify the variants as ranging from activating to damaging, prioritising them for experimental studies.
Highlights
Ligands using unbiased molecular dynamics simulations achieving poses matching those determined crystallographically[18]
Electron microscopy studies have gleaned insights into the association of β 2-adrenergic receptor (β 2AR) with β -arrestin21. β -arrestin is observed to interact by a biphasic mechanism, the first at the C-terminal domain of β 2AR followed by weak interactions with the receptor core
The dbSNP was mined to compile a list of non synonymous single nucleotide polymorphisms (nsSNPs) of the ADRB2 that was further refined based on their deleterious nature
Summary
Ligands using unbiased molecular dynamics simulations achieving poses matching those determined crystallographically[18]. The stabilization of the outward pointing TM helix 6 is thought to be concerted with the flipping of the sidechain of Trp[286] (residue 6.48 of GPCRs as per the Ballesteros Weinstein numbering), called the rotamer toggle switch model (recently called transmission switch model) for receptor activation[27]. This switch has only been observed in experimental studies of rhodopsin[28,29]. Allosteric modulation by phospholipids have been observed experimentally[32] and predicted by simulations[33] This well characterized activation mechanism of the wildtype β 2AR provides a benchmark to compare the dynamics of the natural variants. Our work suggests in vitro testing of these polymorphisms, followed by clinical studies that would reveal their role in health and disease
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