Hybrid Molecular Mechanics/Coarse-Grained Simulations for Structural Prediction of G-Protein Coupled Receptor/Ligand Complexes

Leguèbe, Michael; Nguyen, Chuong; Capece, Luciana; Zung, Hoang; Giorgetti, Alejandro; Carloni, Paolo

doi:10.1371/journal.pone.0047332

Cited by 45 publications

(95 citation statements)

References 38 publications

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“…16 In a few pioneering works, the fixed boundary between resolutions may even occur at a fixed place within a single biomolecule. 17,18 Such fixedresolution multiscale schemes have successfully been used to reach longer length-and time scales than previously possible, providing insights into processes and phenomena including cellular crowding, 12 protein folding, 14,[19][20][21] ligand binding, 22 and structural dynamics of DNA-protein complexes. 23 However, the degrees of freedom to be eliminated in such multiscale schemes must be carefully chosen based on the particular system under consideration.…”

Section: Introductionmentioning

confidence: 99%

Adaptive resolution simulation of a biomolecule and its hydration shell: Structural and dynamical properties

Fogarty

Potestio

Kremer

2015

The Journal of Chemical Physics

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A fully atomistic modelling of many biophysical and biochemical processes at biologically relevant length- and time scales is beyond our reach with current computational resources, and one approach to overcome this difficulty is the use of multiscale simulation techniques. In such simulations, when system properties necessitate a boundary between resolutions that falls within the solvent region, one can use an approach such as the Adaptive Resolution Scheme (AdResS), in which solvent particles change their resolution on the fly during the simulation. Here, we apply the existing AdResS methodology to biomolecular systems, simulating a fully atomistic protein with an atomistic hydration shell, solvated in a coarse-grained particle reservoir and heat bath. Using as a test case an aqueous solution of the regulatory protein ubiquitin, we first confirm the validity of the AdResS approach for such systems, via an examination of protein and solvent structural and dynamical properties. We then demonstrate how, in addition to providing a computational speedup, such a multiscale AdResS approach can yield otherwise inaccessible physical insights into biomolecular function. We use our methodology to show that protein structure and dynamics can still be correctly modelled using only a few shells of atomistic water molecules. We also discuss aspects of the AdResS methodology peculiar to biomolecular simulations.

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Section: Introductionmentioning

confidence: 99%

Adaptive resolution simulation of a biomolecule and its hydration shell: Structural and dynamical properties

Fogarty

Potestio

Kremer

2015

The Journal of Chemical Physics

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“…Recently, we have developed a combined atomistic-coarse grained approach [14] for structural predictions of agonist- and antagonist- GPCR complexes, the Molecular Mechanics/Coarse-Grained (MM/CG) molecular dynamics [15], [16]. Here, the ligand, the solvent surrounding it and the binding cavity are represented with an atomistic force field, while the rest of the protein frame is described using a Go-like [17] CG representation (Fig.…”

Section: Introductionmentioning

confidence: 99%

Coarse-Grained/Molecular Mechanics of the TAS2R38 Bitter Taste Receptor: Experimentally-Validated Detailed Structural Prediction of Agonist Binding

et al. 2013

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Bitter molecules in humans are detected by ∼25 G protein-coupled receptors (GPCRs). The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC) and propylthiouracil (PROP). We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG) method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so-called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking.

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“…The methodology automatized in GOMoDo has been already used to structurally characterize ligand-GPCRs adducts [8,11,44]. To assess the server, we tested GOMoDo by reproducing selected examples of known GPCR-ligand complexes present in the PDB (targets).…”

Section: Application Casesmentioning

confidence: 99%

“…Here we describe three examples of applications (Figure 2): the first example is a simple application using the human beta-2 adrenergic receptor (hβ2AR) that has been previously used by some of us as a test case [44]. The second example is the modeling of human dopamine D3 receptor (hD3R), a slightly more complex case because of the low sequence identity between the receptor and the templates.…”

Section: Application Casesmentioning

confidence: 99%

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GOMoDo: A GPCRs Online Modeling and Docking Webserver

et al. 2013

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G-protein coupled receptors (GPCRs) are a superfamily of cell signaling membrane proteins that include >750 members in the human genome alone. They are the largest family of drug targets. The vast diversity and relevance of GPCRs contrasts with the paucity of structures available: only 21 unique GPCR structures have been experimentally determined as of the beginning of 2013. User-friendly modeling and small molecule docking tools are thus in great demand. While both GPCR structural predictions and docking servers exist separately, with GOMoDo (GPCR Online M odeling and D ocking), we provide a web server to seamlessly model GPCR structures and dock ligands to the models in a single consistent pipeline. GOMoDo can automatically perform template choice, homology modeling and either blind or information-driven docking by combining together proven, state of the art bioinformatic tools. The web server gives the user the possibility of guiding the whole procedure. The GOMoDo server is freely accessible at http://molsim.sci.univr.it/gomodo.

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Hybrid Molecular Mechanics/Coarse-Grained Simulations for Structural Prediction of G-Protein Coupled Receptor/Ligand Complexes

Cited by 45 publications

References 38 publications

Adaptive resolution simulation of a biomolecule and its hydration shell: Structural and dynamical properties

Adaptive resolution simulation of a biomolecule and its hydration shell: Structural and dynamical properties

Coarse-Grained/Molecular Mechanics of the TAS2R38 Bitter Taste Receptor: Experimentally-Validated Detailed Structural Prediction of Agonist Binding

GOMoDo: A GPCRs Online Modeling and Docking Webserver

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