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Recent progress in the study of G protein-coupled receptors with molecular dynamics computer simulations. Biochim Biophys Acta

Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 03/2011; 1808(7):1868-78. DOI: 10.1016/j.bbamem.2011.03.010
Source: PubMed

ABSTRACT G protein-coupled receptors (GPCRs) are a large, biomedically important family of proteins, and the recent explosion of new high-resolution structural information about them has provided an enormous opportunity for computational modeling to make major contributions. In particular, molecular dynamics simulations have become a driving factor in many areas of GPCR biophysics, improving our understanding of lipid-protein interaction, activation mechanisms, and internal hydration. Given that computers will continue to get faster and more structures will be solved, the importance of computational methods will only continue to grow, particularly as simulation research is more closely coupled to experiment.

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    • "GPCRs, like other integral membrane proteins, require a lipid membrane environment to remain folded. Thus, it is challenging to find conditions to over express and purify them [5]. The Beta 3-adrenergic receptor (b3-AR) belongs to the beta adrenergic receptor subfamily Class A GPCR. "
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    ABSTRACT: Beta 3-Adrenergic receptors (β3-AR), belonging to the G-protein coupled receptor family, are known to be involved in important physiological functions as intestinal smooth muscle relaxation, glucose homeostasis etc. Detailed insight into the mechanistic mode of β3-AR is not known. Molecular dynamic simulations (100ns) were performed on the 3-D molecular model of β3-AR and complexes of β3-AR with potential agonists embedded in 2-dipalmitoyl-sn-phosphocholine (DPPC) bilayer - water system using OPLS (Optimized Potentials for Liquid Simulations) force field to gain structural insight into β3-AR. The detailed structural analysis of the molecular dynamic trajectories reveal that the helical bundle conformations remain well preserved to maintain a conformation similar to the other X-ray solved G-protein coupled receptors, whereas significant flexibility is observed in intracellular and the extracellular loops region. The formation of extensive intra helical and water mediated H-bonds, and aromatic stacking interactions play a key role in stabilizing the transmembrane helical bundles. These interactions might be specific to the functional motifs such as D(E)RY, CWxP, S(N)LAxAD, SxxxS and NPxxY motifs which provide structural constraints on the β3-AR. The compound 3, 4 and 6 are proposed to act as scaffolds for potential agonists for β3-AR based on stereochemical and energetic considerations. In lieu of the lack of the crystal structure available, the findings of the simulation study provides more comprehensive picture of the functional properties of the β3-AR.
    Biochimie 06/2014; 101. DOI:10.1016/j.biochi.2014.01.016 · 3.12 Impact Factor
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    • "This is broken on activation, and there has been some discussion on whether a proton moves from Glu181 in ECL2 to Glu113 3.28 . However, most theoretical studies imply that both glutamates retain the normal deprotonated ionization state during activation (Grossfield, 2011; Mertz et al., 2012). By default, most modeling programs protonate histidine at the delta position rather than the epsilon position, but see Neri et al. (2010) "
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    ABSTRACT: The most significant advance in modeling GPCR active states has been the β(2)-adrenergic receptor-Gs complex as this essentially transforms active-state modeling into homology modeling. Various different molecular dynamics-based approaches for modeling active states are presented, and a number of key applications discussed. These simulations have given insights into the activation pathway, conformational changes, dimerization, hydration, the ionic lock, ligand binding, protonation, and sodium binding. Crystallography and simulations have shown that the presence of agonist alone is unlikely to be sufficient to form the active state and that restraints applied to the G protein-binding region are required. The role of various microswitches in activation is discussed, including the controversial rotamer toggle switch. The importance of explicitly simulating experimental molecular probes to understand activation is highlighted, along with the need to ensure that such molecules are well parameterized. Approaches to loop modeling are discussed. We argue that the role of successful virtual screening against active models should not be overestimated as the main conformational changes on activation occur in the intracellular region.
    Methods in enzymology 01/2013; 522:21-35. DOI:10.1016/B978-0-12-407865-9.00002-9 · 2.19 Impact Factor
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    • "For this purpose, we constructed an atomistic model of the M3R that was further refined using extended molecular dynamics (MD) simulations of the protein embedded in a lipid bilayer. The analysis of the MD trajectories provides a better understanding of the structural features that characterize the ligand-receptor interaction at the orthosteric pocket, the dynamics of the extracellular loops, as well as its putative involvement in ligand binding [10]. Present modeling studies suggest that residues F222 located in the ECL2 and T235 located at the edge of TM5 participate in the recognition of NMS. "
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    ABSTRACT: The present study reports the results of a combined computational and site mutagenesis study designed to provide new insights into the orthosteric binding site of the human M3 muscarinic acetylcholine receptor. For this purpose a three-dimensional structure of the receptor at atomic resolution was built by homology modeling, using the crystallographic structure of bovine rhodopsin as a template. Then, the antagonist N-methylscopolamine was docked in the model and subsequently embedded in a lipid bilayer for its refinement using molecular dynamics simulations. Two different lipid bilayer compositions were studied: one component palmitoyl-oleyl phosphatidylcholine (POPC) and two-component palmitoyl-oleyl phosphatidylcholine/palmitoyl-oleyl phosphatidylserine (POPC-POPS). Analysis of the results suggested that residues F222 and T235 may contribute to the ligand-receptor recognition. Accordingly, alanine mutants at positions 222 and 235 were constructed, expressed, and their binding properties determined. The results confirmed the role of these residues in modulating the binding affinity of the ligand.
    BioMed Research International 02/2012; 2012:789741. DOI:10.1155/2012/789741 · 2.71 Impact Factor
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