Volume 6 Issue 1, January 2014

Volume 6 Issue 1

G-protein-coupled receptors lie across cell membranes and transmit messages from the outside of cells — initiated through ligand binding — to the inside. Molecular dynamics simulations have proved helpful in understanding how they work at an atomistic level but are very computationally intensive. Now Kohlhoff, Altman, Pande and co-workers describe an approach to performing and analysing lengthy molecular dynamics simulations, which involves the stitching together of many shorter independent simulations run using Google's Exacycle cloud computing platform. The cover shows an artistic interpretation of a view from the cell exterior of a G-protein-coupled receptor interacting with the partial inverse agonist carazolol.Article p15;News & Views p7IMAGE: THOR LEWISCOVER DESIGN: ALEX WING


  • Thesis |

    Michelle Francl takes a serious look at whether we should indulge in scientific humour.

    • Michelle Francl

Research Highlights


News and Views

  • News & Views |

    Lengthy molecular dynamics simulations of complex systems at the atomic scale usually require supercomputers. Now, by stitching together many shorter independent simulations run 'in the cloud', this requirement has been circumvented, allowing two milliseconds of the dynamics of a G-protein-coupled receptor to be simulated.

    • Xavier Deupi
  • News & Views |

    Quantitatively studying how the rate of a chemical reaction is affected by a reactant's atomic-scale environment is extremely challenging. This has now been achieved at the single-molecule level using scanning tunnelling microscopy to monitor tautomerization in an atomically well-defined environment.

    • Peter Liljeroth
  • News & Views |

    Fluorine imparts many drugs with beneficial properties, however, the synthesis of fluorinated complex natural products is challenging. Biosynthetic strategies and recent experimental precedents have paved the way for bioengineered fluorinated polyketides.

    • Peter A. Jordan
    •  & Bradley S. Moore
  • News & Views |

    One-pot processes in which a single catalyst carries out several reactions are attractive, but typically promote the formation of by-products as well as the desired ones, and are not amenable to optimization of the individual transformations. Now, these issues have been overcome by separating the catalytic processes in time.

    • Sarah Abou-Shehada
    •  & Jonathan M. J. Williams
  • News & Views |

    Replication of the HIV-1 viral genome can be inhibited by a protein known as APOBEC3G, via two seemingly contradictory mechanisms. Now, the molecular conundrum behind these two processes has been resolved.

    • Graeme A. King
    •  & Gijs J. L. Wuite


  • Article |

    Two milliseconds of molecular dynamics simulations of a major drug-target G-protein-coupled receptor (GPCR) has been carried out using Google's Exacycle cloud computing platform. Markov state models were used to aggregate independent simulations into a statistical model that provides an atomistic description of GPCR ligand-modulated activation pathways.

    • Kai J. Kohlhoff
    • , Diwakar Shukla
    • , Morgan Lawrenz
    • , Gregory R. Bowman
    • , David E. Konerding
    • , Dan Belov
    • , Russ B. Altman
    •  & Vijay S. Pande
  • Article |

    Multifunctional catalysts typically process substrates and intermediates concurrently. Here, a strategy is described to separate catalytic activities in the time domain (temporal separation). Application of this strategy has led to the development of a method to effect the anti-Markovnikov reductive functionalization of terminal alkynes; such an approach may facilitate the development of other synthetic reaction cascades.

    • Le Li
    •  & Seth B. Herzon
  • Article |

    HIV-1 replication is inhibited by the enzyme APOBEC3G via two separate mechanisms. A deamination mechanism requires rapid binding and release of single-stranded DNA (ssDNA), whereas a roadblock mechanism requires slow binding. Now APOBEC3G has been shown to initially bind ssDNA with rapid on–off rates. The enzyme subsequently converts via oligomerization to a slowly dissociating binding mode, which, it is proposed, inhibits reverse transcription.

    • Kathy R. Chaurasiya
    • , Micah J. McCauley
    • , Wei Wang
    • , Dominic F. Qualley
    • , Tiyun Wu
    • , Shingo Kitamura
    • , Hylkje Geertsema
    • , Denise S. B. Chan
    • , Amber Hertz
    • , Yasumasa Iwatani
    • , Judith G. Levin
    • , Karin Musier-Forsyth
    • , Ioulia Rouzina
    •  & Mark C. Williams
  • Article |

    An aryne intermediate produced by a hexadehydro-Diels–Alder reaction is shown to engage in an unusual — and before this work rare and inefficient — aromatic ene reaction to produce an isotoluene. This second reactive intermediate can then engage an external enophile resulting in a conjunctive cascade in which four C–C bonds and three rings are created without involvement of reagents or generation of by-products.

    • Dawen Niu
    •  & Thomas R. Hoye
  • Article |

    The rate of an intramolecular hydrogen transfer reaction in a single porphycene molecule resting on a copper surface can be controlled by placing a copper adatom close to it. Cooperativity effects are also observed in rows of porphycene molecules, where the reaction rate of each individual molecule depends on the precise tautomer state of its neighbours.

    • Takashi Kumagai
    • , Felix Hanke
    • , Sylwester Gawinkowski
    • , John Sharp
    • , Konstantinos Kotsis
    • , Jacek Waluk
    • , Mats Persson
    •  & Leonhard Grill
  • Article |

    A palladium-catalysed, highly enantio- and diastereoselective [3 + 2] cycloaddition reaction to produce densely functionalized pyrrolidine frameworks is developed by exploiting a new phosphine ligand with a chiral ammonium salt component. Rigorous control of the individual absolute stereochemistry of three contiguous stereocentres, including vicinal all-carbon quaternary stereocentres, is possible using this methodology.

    • Kohsuke Ohmatsu
    • , Naomichi Imagawa
    •  & Takashi Ooi
  • Article |

    Polynitrogen compounds are of interest on a fundamental level and as potential high-energy-density materials. A crystalline solid that consists of two isomeric forms of N8 molecules held together by weak van der Waals interactions has now been predicted to exist, and to be stable even at low pressures.

    • Barak Hirshberg
    • , R. Benny Gerber
    •  & Anna I. Krylov
  • Article |

    Emulating the biogenesis of natural products, a synthetic strategy is described in which an achiral multipotent intermediate reacts through three distinct [4 + 2] cyclizations and two types of redox-mediated annulation. This results in divergent access to natural product-like scaffolds in 6–9 steps. The efficiency of this approach is highlighted in the total syntheses of three natural products.

    • Haruki Mizoguchi
    • , Hideaki Oikawa
    •  & Hiroki Oguri
  • Article |

    Identification of glycosylation patterns is complicated by the lack of sensitive analytical techniques that can distinguish between epimeric carbohydrates. It has now been shown that ion-mobility tandem mass spectrometry of ions derived from glycopeptides and oligosaccharides enables glycan stereochemistry to be determined, highlighting the potential of this technique for sequencing complex carbohydrates on cell surfaces.

    • P. Both
    • , A. P. Green
    • , C. J. Gray
    • , R. Šardzík
    • , J. Voglmeir
    • , C. Fontana
    • , M. Austeri
    • , M. Rejzek
    • , D. Richardson
    • , R. A. Field
    • , G. Widmalm
    • , S. L. Flitsch
    •  & C. E. Eyers
  • Article |

    The presence of RNA G-quadruplex structures in human cells using a structure-specific antibody is demonstrated. Using small molecules, the selective stabilization of cytoplasmic RNA G-quadruplexes versus nuclear DNA G-quadruplexes is demonstrated. These findings validate the existence of RNA G-quadruplexes and their specific targeting by small molecules within a cellular context.

    • Giulia Biffi
    • , Marco Di Antonio
    • , David Tannahill
    •  & Shankar Balasubramanian

In Your Element

  • In Your Element |

    Markku Räsänen remembers making a neutral compound featuring argon, and ponders on the reactivity of this inert element.

    • Markku Räsänen