Cross-Over between Discrete and Continuous Protein Structure Space: Insights into Automatic Classification and Networks of Protein Structures

Structural classifications of proteins assume the existence of the fold, which is an intrinsic equivalence class of protein domains. Here, we test in which conditions such an equivalence class is compatible with objective similarity measures. We base our analysis on the transitive property of the equivalence relationship, requiring that similarity of A with B and B with C implies that A and C are also similar. Divergent gene evolution leads us to expect that the transitive property should approximately hold. However, if protein domains are a combination of recurrent short polypeptide fragments, as proposed by several authors, then similarity of partial fragments may violate the transitive property, favouring the continuous view of the protein structure space. We propose a measure to quantify the violations of the transitive property when a clustering algorithm joins elements into clusters, and we find out that such violations present a well defined and detectable cross-over point, from an approximately transitive regime at high structure similarity to a regime with large transitivity violations and large differences in length at low similarity. We argue that protein structure space is discrete and hierarchic classification is justified up to this cross-over point, whereas at lower similarities the structure space is continuous and it should be represented as a network. We have tested the qualitative behaviour of this measure, varying all the choices involved in the automatic classification procedure, i.e., domain decomposition, alignment algorithm, similarity score, and clustering algorithm, and we have found out that this behaviour is quite robust. The final classification depends on the chosen algorithms. We used the values of the clustering coefficient and the transitivity violations to select the optimal choices among those that we tested. Interestingly, this criterion also favours the agreement between automatic and expert classifications. As a domain set, we have selected a consensus set of 2,890 domains decomposed very similarly in SCOP and CATH. As an alignment algorithm, we used a global version of MAMMOTH developed in our group, which is both rapid and accurate. As a similarity measure, we used the size-normalized contact overlap, and as a clustering algorithm, we used average linkage. The resulting automatic classification at the cross-over point was more consistent than expert ones with respect to the structure similarity measure, with 86% of the clusters corresponding to subsets of either SCOP or CATH superfamilies and fewer than 5% containing domains in distinct folds according to both SCOP and CATH. Almost 15% of SCOP superfamilies and 10% of CATH superfamilies were split, consistent with the notion of fold change in protein evolution. These results were qualitatively robust for all choices that we tested, although we did not try to use alignment algorithms developed by other groups. Folds defined in SCOP and CATH would be completely joined in the regime of large transitivity violations where clustering is more arbitrary. Consistently, the agreement between SCOP and CATH at fold level was lower than their agreement with the automatic classification obtained using as a clustering algorithm, respectively, average linkage (for SCOP) or single linkage (for CATH). The networks representing significant evolutionary and structural relationships between clusters beyond the cross-over point may allow us to perform evolutionary, structural, or functional analyses beyond the limits of classification schemes. These networks and the underlying clusters are available at http://ub.cbm.uam.es/research/ProtNet.ph

Drug discovery against H1N1 virus (influenza A virus) via computational virtual screening approach

The H1N1 virus is the causative agent of the recent outbreak of Swine flu pandemic. Neuraminidase is an enzyme that cleave glycosidic linkage of neuraminic acid on viral cell surface and is known to occur as antigen determinant to evoke immune response in host cell. It plays an important role in life cycle of influenza virus. Inhibitors of neuraminidase are, therefore, believed to have a potential in development of new drugs against swine flu. Using a recently published model structure of neuraminidase, we have carried out virtual screening of 70 compounds obtained from Ligand databases. The ligands library also included 57 natural plant metabolites from medicinal plants. The virtual screening was performed via PatchDock & GemDock softwares. Two of the plant metabolites, Hesperidin & Narirutin showed significantly higher docking score than the currently marketed anti-influenza drug Oseltamivir (Tamiflu)

Protein local conformations arise from a mixture of Gaussian distributions

The classical approaches for protein structure prediction rely either on homology of the protein sequence with a template structure or on ab initio calculations for energy minimization. These methods suffer from disadvantages such as the lack of availability of homologous template structures or intractably large conformational search space, respectively. The recently proposed fragment library based approaches first predict the local structures, which can be used in conjunction with the classical approaches of protein structure prediction. The accuracy of the predictions is dependent on the quality of the fragment library. In this work, we have constructed a library of local conformation classes purely based on geometric similarity. The local conformations are represented using Geometric Invariants, properties that remain unchanged under transformations such as translation and rotation, followed by dimension reduction via principal component analysis. The local conformations are then modeled as a mixture of Gaussian probability distribution functions (PDF). Each one of the Gaussian PDF's corresponds to a conformational class with the centroid representing the average structure of that class. We find 46 classes when we use an octapeptide as a unit of local conformation. The protein 3-D structure can now be described as a sequence of local conformational classes. Further, it was of interest to see whether the local conformations can be predicted from the amino acid sequences. To that end, we have analyzed the correlation between sequence features and the conformational classes

Detecting Protein Candidate Fragments Using a Structural Alphabet Profile Comparison Approach

Predicting accurate fragments from sequence has recently become a critical step for protein structure modeling, as protein fragment assembly techniques are presently among the most efficient approaches for de novo prediction. A key step in these approaches is, given the sequence of a protein to model, the identification of relevant fragments - candidate fragments - from a collection of the available 3D structures. These fragments can then be assembled to produce a model of the complete structure of the protein of interest. The search for candidate fragments is classically achieved by considering local sequence similarity using profile comparison, or threading approaches. In the present study, we introduce a new profile comparison approach that, instead of using amino acid profiles, is based on the use of predicted structural alphabet profiles, where structural alphabet profiles contain information related to the 3D local shapes associated with the sequences. We show that structural alphabet profile-profile comparison can be used efficiently to retrieve accurate structural fragments, and we introduce a fully new protocol for the detection of candidate fragments. It identifies fragments specific of each position of the sequence and of size varying between 6 and 27 amino-acids. We find it outperforms present state of the art approaches in terms (i) of the accuracy of the fragments identified, (ii) the rate of true positives identified, while having a high coverage score. We illustrate the relevance of the approach on complete target sets of the two previous Critical Assessment of Techniques for Protein Structure Prediction (CASP) rounds 9 and 10. A web server for the approach is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/SAFrag

A Nearby Repeating Fast Radio Burst in the Direction of M81

We report on the discovery of FRB 20200120E, a repeating fast radio burst (FRB) with low dispersion measure (DM), detected by the Canadian Hydrogen Intensity Mapping Experiment (CHIME)/FRB project. The source DM of 87.82 pc cm$^{-3}$ is the lowest recorded from an FRB to date, yet is significantly higher than the maximum expected from the Milky Way interstellar medium in this direction (~ 50 pc cm$^{-3}$). We have detected three bursts and one candidate burst from the source over the period 2020 January-November. The baseband voltage data for the event on 2020 January 20 enabled a sky localization of the source to within $\simeq$ 14 sq. arcmin (90% confidence). The FRB localization is close to M81, a spiral galaxy at a distance of 3.6 Mpc. The FRB appears on the outskirts of M81 (projected offset $\sim$ 20 kpc) but well inside its extended HI and thick disks. We empirically estimate the probability of chance coincidence with M81 to be $< 10^{-2}$. However, we cannot reject a Milky Way halo origin for the FRB. Within the FRB localization region, we find several interesting cataloged M81 sources and a radio point source detected in the Very Large Array Sky Survey (VLASS). We searched for prompt X-ray counterparts in Swift/BAT and Fermi/GBM data, and for two of the FRB 20200120E bursts, we rule out coincident SGR 1806$-$20-like X-ray bursts. Due to the proximity of FRB 20200120E, future follow-up for prompt multi-wavelength counterparts and sub-arcsecond localization could be constraining of proposed FRB models

No Evidence for Galactic Latitude Dependence of the Fast Radio Burst Sky Distribution

Abstract We investigate whether the sky rate of fast radio bursts (FRBs) depends on Galactic latitude using the first catalog of FRBs detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst (CHIME/FRB) Project. We first select CHIME/FRB events above a specified sensitivity threshold in consideration of the radiometer equation, and then we compare these detections with the expected cumulative time-weighted exposure using Anderson–Darling and Kolmogorov–Smirnov tests. These tests are consistent with the null hypothesis that FRBs are distributed without Galactic latitude dependence (p-values distributed from 0.05 to 0.99, depending on completeness threshold). Additionally, we compare rates in intermediate latitudes (∣b∣ &lt; 15°) with high latitudes using a Bayesian framework, treating the question as a biased coin-flipping experiment–again for a range of completeness thresholds. In these tests the isotropic model is significantly favored (Bayes factors ranging from 3.3 to 14.2). Our results are consistent with FRBs originating from an isotropic population of extragalactic sources.</jats:p

PTF10iya: a short-lived, luminous flare from the nuclear region of a star-forming galaxy

We present the discovery and characterization of PTF10iya, a short-lived (Δt≈ 10d, with an optical decay rate of ∼0.3magd -1), luminous (mag) transient source found by the Palomar Transient Factory. The ultraviolet/optical spectral energy distribution is reasonably well fitted by a blackbody with T≈ (1-2) × 10 4K and peak bolometric luminosity L BB≈ (1-5) × 10 44ergs -1 (depending on the details of the extinction correction). A comparable amount of energy is radiated in the X-ray band that appears to result from a distinct physical process. The location of PTF10iya is consistent with the nucleus of a star-forming galaxy (z= 0.22405 ± 0.00006) to within 350mas (99.7per cent confidence radius), or a projected distance of less than 1.2kpc. At first glance, these properties appear reminiscent of the characteristic 'big blue bump' seen in the near-ultraviolet spectra of many active galactic nuclei (AGNs). However, emission-line diagnostics of the host galaxy, along with a historical light curve extending back to 2007, show no evidence for AGN-like activity. We therefore consider whether the tidal disruption of a star by an otherwise quiescent supermassive black hole may account for our observations. Though with limited temporal information, PTF10iya appears broadly consistent with the predictions for the early 'super-Eddington' phase of a solar-type star being disrupted by a ∼10 7M ⊙ black hole. Regardless of the precise physical origin of the accreting material, the large luminosity and short duration suggest that otherwise quiescent galaxies can transition extremely rapidly to radiate near the Eddington limit; many such outbursts may have been missed by previous surveys lacking sufficient cadence. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS