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Beyond modeling: all-atom olfactory receptor model simulations.

ABSTRACT: Olfactory receptors (ORs) are a type of GTP-binding protein-coupled receptor (GPCR). These receptors are responsible for mediating the sense of smell through their interaction with odor ligands. OR-odorant interactions marks the first step in the process that leads to olfaction. Computational studies on model OR structures can generate focused and novel hypotheses for further bench investigation by providing a view of these interactions at the molecular level beyond inferences that are drawn merely from static docking. Here we have shown the specific advantages of simulating the dynamic environment associated with OR-odorant interactions. We present a rigorous protocol which ranges from the creation of a computationally derived model of an olfactory receptor to simulating the interactions between an OR and an odorant molecule. Given the ubiquitous occurrence of GPCRs in the membranes of cells, we anticipate that our OR-developed methodology will serve as a model for the computational structural biology of all GPCRs.

SUBMITTER: Lai PC

PROVIDER: S-EPMC3342527 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Beyond modeling: all-atom olfactory receptor model simulations.

Lai Peter C PC Crasto Chiquito J CJ

Frontiers in genetics 20120503

Olfactory receptors (ORs) are a type of GTP-binding protein-coupled receptor (GPCR). These receptors are responsible for mediating the sense of smell through their interaction with odor ligands. OR-odorant interactions marks the first step in the process that leads to olfaction. Computational studies on model OR structures can generate focused and novel hypotheses for further bench investigation by providing a view of these interactions at the molecular level beyond inferences that are drawn mer ...[more]

PMID: 22563330

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Project description:N-methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family that mediate excitatory synaptic transmission in the central nervous system. The channels of NMDARs are permeable to Ca2+ but blocked by Mg2+, distinctive properties that underlie essential brain processes such as induction of synaptic plasticity. However, due to limited structural information about the NMDAR transmembrane ion channel forming domain, the mechanism of divalent cation permeation and block is understood poorly. In this paper we developed an atomistic model of the transmembrane domain (TMD) of NMDARs composed of GluN1 and GluN2A subunits (GluN1/2A receptors). The model was generated using (a) a homology model based on the structure of the NaK channel and a partially resolved structure of an AMPA receptor (AMPAR), and (b) a partially resolved X-ray structure of GluN1/2B NMDARs. Refinement and extensive Molecular Dynamics (MD) simulations of the NMDAR TMD model were performed in explicit lipid bilayer membrane and water. Targeted MD with simulated annealing was introduced to promote structure refinement. Putative positions of the Mg2+ and Ca2+ ions in the ion channel divalent cation binding site are proposed. Differences in the structural and dynamic behavior of the channel protein in the presence of Mg2+ or Ca2+ are analyzed. NMDAR protein conformational flexibility was similar with no ion bound to the divalent cation binding site and with Ca2+ bound, whereas Mg2+ binding reduced protein fluctuations. While bound at the binding site both ions retained their preferred ligand coordination numbers: 6 for Mg2+, and 7-8 for Ca2+. Four asparagine side chain oxygens, a back-bone oxygen, and a water molecule participated in binding a Mg2+ ion. The Ca2+ ion first coordination shell ligands typically included four to five side-chain oxygen atoms of the binding site asparagine residues, two water molecules and zero to two backbone oxygens of the GluN2B subunits. These results demonstrate the importance of high-resolution channel structures for elucidation of mechanisms of NMDAR permeation and block.

Dataset Information

Beyond modeling: all-atom olfactory receptor model simulations.

Publications

Beyond modeling: all-atom olfactory receptor model simulations.

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