A Kinetic Model of Trp-Cage Folding from Multiple Biased Molecular Dynamics Simulations

Trp-cage is a designed 20-residue polypeptide that, in spite of its size, shares several features with larger globular proteins. Although the system has been intensively investigated experimentally and theoretically, its folding mechanism is not yet fully understood. Indeed, some experiments suggest a two-state behavior, while others point to the presence of intermediates. In this work we show that the results of a bias-exchange metadynamics simulation can be used for constructing a detailed thermodynamic and kinetic model of the system. The model, although constructed from a biased simulation, has a quality similar to those extracted from the analysis of long unbiased molecular dynamics trajectories. This is demonstrated by a careful benchmark of the approach on a smaller system, the solvated Ace-Ala3-Nme peptide. For the Trp-cage folding, the model predicts that the relaxation time of 3100 ns observed experimentally is due to the presence of a compact molten globule-like conformation. This state has an occupancy of only 3% at 300 K, but acts as a kinetic trap. Instead, non-compact structures relax to the folded state on the sub-microsecond timescale. The model also predicts the presence of a state at of 4.4 Å from the NMR structure in which the Trp strongly interacts with Pro12. This state can explain the abnormal temperature dependence of the and chemical shifts. The structures of the two most stable misfolded intermediates are in agreement with NMR experiments on the unfolded protein. Our work shows that, using biased molecular dynamics trajectories, it is possible to construct a model describing in detail the Trp-cage folding kinetics and thermodynamics in agreement with experimental data

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector

First measurement of the differential branching fraction and C ⁣PC\!P asymmetry of the B±→π±μ+μ−B^\pm\to\pi^\pm\mu^+\mu^- decay

The differential branching fraction with respect to the dimuon invariant mass squared, and the $C\!P$ asymmetry of the $B^\pm\to\pi^\pm\mu^+\mu^-$ decay are measured for the first time. The CKM matrix elements $|V_{td}|$ and $|V_{ts}|$, and the ratio $|V_{td}/V_{ts}|$ are determined. The analysis is performed using proton-proton collision data corresponding to an integrated luminosity of 3.0 fb$^{-1}$, collected by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The total branching fraction and $C\!P$ asymmetry of $B^\pm\to\pi^\pm\mu^+\mu^-$ decays are measured to be \begin{eqnarray} \mathcal{B}(B^\pm\to\pi^\pm\mu^+\mu^-) &=& (1.83 \pm 0.24 \pm 0.05) \times 10^{-8}\,\,\,\mathrm{and} \nonumber\\ \mathcal{A}_{C\!P}(B^\pm\to\pi^\pm\mu^+\mu^-) &=& -0.11 \pm 0.12 \pm 0.01\,, \nonumber \end{eqnarray} where the first uncertainties are statistical and the second are systematic. These are the most precise measurements of these observables to date, and they are compatible with the predictions of the Standard Model

Search for the B 0s → η′ϕ decay

A search for the charmless $B^{0}_{s} \to \eta^{\prime}\phi$ decay is performed using $pp$ collision data collected by the LHCb experiment at centre-of-mass energies of $7$ and $8$ TeV, corresponding to an integrated luminosity of 3 fb$^{-1}$. No signal is observed and upper limits on the $B^{0}_{s} \to \eta^{\prime}\phi$ branching fraction are set to $0.82\times 10^{-6}$ at $90\%$ and $1.01\times 10^{-6}$ at $95\%$ confidence level.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-060.htm

Measurement of CPCP observables in B±→DK∗±B^{\pm} \rightarrow D K^{*\pm} decays using two- and four-body DD final states

Measurements of CP observables in B$^{±}$ → DK$^{*±}$ decays are presented, where D denotes a superposition of D$^{0}$ and ${\overline{D}}^0$ meson states. Decays of the D meson to K$^{−}$ π$^{+}$, K$^{−}$ K$^{+}$, π$^{−}$ π$^{+}$, K$^{−}$ π$^{+}$ π$^{−}$ π$^{+}$ and π$^{−}$ π$^{+}$ π$^{−}$ π$^{+}$ are used and the K$^{*±}$ meson is reconstructed in the K$_{S}^{0}$ π$^{±}$ final state. This analysis uses a data sample of pp collisions collected with the LHCb experiment, corresponding to integrated luminosities of 1 fb$^{−1}$, 2 fb$^{−1}$ and 1.8 fb$^{−1}$ at centre-of-mass energies $\sqrt{s}=7$ TeV, 8 TeV and 13 TeV, respectively. The sensitivity of the results to the CKM angle γ is discussed.Measurements of $CP$ observables in $B^{\pm} \rightarrow D K^{*\pm}$ decays are presented, where $D$ denotes a superposition of $D^0$ and $\overline{D^0}$ meson states. Decays of the $D$ meson to $K^{-}\pi^{+}$, $K^{-}K^{+}$, $\pi^{-}\pi^{+}$, $K^{-}\pi^{+}\pi^{-}\pi^{+}$ and $\pi^{-}\pi^{+}\pi^{-}\pi^{+}$ are used and the $K^{*\pm}$ meson is reconstructed in the $K^{0}_{\mathrm{S}}\pi^{\pm}$ final state. This analysis uses a data sample of $pp$ collisions collected with the LHCb experiment, corresponding to integrated luminosities of 1 $\mathrm{fb}^{-1}$, 2 $\mathrm{fb}^{-1}$ and 1.8 $\mathrm{fb}^{-1}$ at centre-of-mass energies $\sqrt{s} =$ 7 TeV, 8 TeV and 13 TeV, respectively. The sensitivity of the results to the CKM angle $\gamma$ is discussed