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Understanding the influence of lipid bilayers and ligand molecules in determining the conformational dynamics of somatostatin receptor 2.

ABSTRACT: Somatostatin receptor 2 (SSTR2) is a G-protein coupled receptor (GPCR) that controls numerous cellular processes including cell-to-cell signaling. In this study, we report how the lipid and ligand molecules influence the conformational dynamics of the membrane-bound SSTR2. Molecular simulations of different holo and apoenzyme complexes of SSTR2 in the presence and absence of a lipid bilayer were performed, observed, and correlated with previously reported studies. We identified the important SSTR2 residues that take part in the formation of the SSTR2-ligand complex. On analyzing the molecular simulation trajectories, we identified that the residue D3.32 is crucial in determining the bioactive conformation of SSTR2 ligands in the binding site. Based on the results, we suggest that designing a novel SSTR2 ligand with an H-bond donor group at the R1 position, and hydrophobic groups at R2 and R3 might have higher activity and SSTR2-selectivity. We analyzed the simulated systems to identify other important structural features involved in SSTR2-ligand binding and to observe the different conformational changes that occur in the protein after the ligand binding. Additionally, we studied the conformational dynamics of N- and C-terminal regions of SSTR2 in the presence and absence of the lipid bilayer. Both the systems were compared to understand the influence of lipid molecules in the formation of secondary structural domains by these extracellular regions. The comparative study revealed that the secondary structural elements formed by C-terminal residues in presence of lipid molecules is crucial for the functioning of SSTR2. Our study results highlight the structural complexities involved in the functioning of SSTR upon binding with the ligands in the presence and absence of lipid bilayer, which is essential for designing novel drug targets.

SUBMITTER: Nagarajan SK

PROVIDER: S-EPMC8027056 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Gramicidin A (gA) is a 15-amino-acid antibiotic peptide with an alternating L-D sequence, which forms (dimeric) bilayer-spanning, monovalent cation channels in biological membranes and synthetic bilayers. We performed molecular dynamics simulations of gA dimers and monomers in all-atom, explicit dilauroylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers. The variation in acyl chain length among these different phospholipids provides a way to alter gA-bilayer interactions by varying the bilayer hydrophobic thickness, and to determine the influence of hydrophobic mismatch on the structure and dynamics of both gA channels (and monomeric subunits) and the host bilayers. The simulations show that the channel structure varied little with changes in hydrophobic mismatch, and that the lipid bilayer adapts to the bilayer-spanning channel to minimize the exposure of hydrophobic residues. The bilayer thickness, however, did not vary monotonically as a function of radial distance from the channel. In all simulations, there was an initial decrease in thickness within 4-5 Å from the channel, which was followed by an increase in DOPC and POPC or a further decrease in DLPC and DMPC bilayers. The bilayer thickness varied little in the monomer simulations-except one of three independent simulations for DMPC and all three DLPC simulations, where the bilayer thinned to allow a single subunit to form a bilayer-spanning water-permeable pore. The radial dependence of local lipid area and bilayer compressibility is also nonmonotonic in the first shell around gA dimers due to gA-phospholipid interactions and the hydrophobic mismatch. Order parameters, acyl chain dynamics, and diffusion constants also differ between the lipids in the first shell and the bulk. The lipid behaviors in the first shell around gA dimers are more complex than predicted from a simple mismatch model, which has implications for understanding the energetics of membrane protein-lipid interactions.

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Understanding the influence of lipid bilayers and ligand molecules in determining the conformational dynamics of somatostatin receptor 2.

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