Deciphering Protein–Protein Interactions. Part II. Computational Methods to Predict Protein and Domain Interaction Partners

Recent advances in high-throughput experimental methods for the identification of protein interactions have resulted in a large amount of diverse data that are somewhat incomplete and contradictory. As valuable as they are, such experimental approaches studying protein interactomes have certain limitations that can be complemented by the computational methods for predicting protein interactions. In this review we describe different approaches to predict protein interaction partners as well as highlight recent achievements in the prediction of specific domains mediating protein-protein interactions. We discuss the applicability of computational methods to different types of prediction problems and point out limitations common to all of them

Long-term trends in evolution of indels in protein sequences

BACKGROUND: In this paper we describe an analysis of the size evolution of both protein domains and their indels, as inferred by changing sizes of whole domains or individual unaligned regions or "spacers". We studied relatively early evolutionary events and focused on protein domains which are conserved among various taxonomy groups. RESULTS: We found that more than one third of all domains have a statistically significant tendency to increase/decrease in size in evolution as judged from the overall domain size distribution as well as from the size distribution of individual spacers. Moreover, the fraction of domains and individual spacers increasing in size is almost twofold larger than the fraction decreasing in size. CONCLUSION: We showed that the tolerance to insertion and deletion events depends on the domain's taxonomy span. Eukaryotic domains are depleted in insertions compared to the overall test set, namely, the number of spacers increasing in size is about the same as the number of spacers decreasing in size. On the other hand, ancient domain families show some bias towards insertions or spacers which grow in size in evolution. Domains from several Gene Ontology categories also demonstrate certain tendencies for insertion or deletion events as inferred from the analysis of spacer sizes

Knowledge-based annotation of small molecule binding sites in proteins

<p>Abstract</p> <p>Background</p> <p>The study of protein-small molecule interactions is vital for understanding protein function and for practical applications in drug discovery. To benefit from the rapidly increasing structural data, it is essential to improve the tools that enable large scale binding site prediction with greater emphasis on their biological validity.</p> <p>Results</p> <p>We have developed a new method for the annotation of protein-small molecule binding sites, using inference by homology, which allows us to extend annotation onto protein sequences without experimental data available. To ensure biological relevance of binding sites, our method clusters similar binding sites found in homologous protein structures based on their sequence and structure conservation. Binding sites which appear evolutionarily conserved among non-redundant sets of homologous proteins are given higher priority. After binding sites are clustered, position specific score matrices (PSSMs) are constructed from the corresponding binding site alignments. Together with other measures, the PSSMs are subsequently used to rank binding sites to assess how well they match the query and to better gauge their biological relevance. The method also facilitates a succinct and informative representation of observed and inferred binding sites from homologs with known three-dimensional structures, thereby providing the means to analyze conservation and diversity of binding modes. Furthermore, the chemical properties of small molecules bound to the inferred binding sites can be used as a starting point in small molecule virtual screening. The method was validated by comparison to other binding site prediction methods and to a collection of manually curated binding site annotations. We show that our method achieves a sensitivity of 72% at predicting biologically relevant binding sites and can accurately discriminate those sites that bind biological small molecules from non-biological ones.</p> <p>Conclusions</p> <p>A new algorithm has been developed to predict binding sites with high accuracy in terms of their biological validity. It also provides a common platform for function prediction, knowledge-based docking and for small molecule virtual screening. The method can be applied even for a query sequence without structure. The method is available at <url>http://www.ncbi.nlm.nih.gov/Structure/ibis/ibis.cgi</url>.</p

Time-richness and phosphatic microsteinkern accumulation in the Cincinnatian (Katian) Ordovician, USA: An example of polycyclic phosphogenic condensation

Millimeter-scale phosphatic steinkern preservation is a feature of the taxonomically enigmatic Early Cambrian “small shelly faunas”, but this style of preservation is not unique to the Cambrian; it is ubiquitous, if infrequently reported, from the Phanerozoic record. The polycyclic phosphogenic condensation (PPC) model envisions both the genesis and concentration of phosphatic microsteinkerns as natural outcomes of shell bed genesis through episodic sediment starvation. This model predicts that more reworked and condensed shell bed limestones will contain more phosphatic microsteinkerns, but that even the least reworked limestones may contain some phosphatic particles. We test this model through examination of vertical thin sections densely collected through a 10-meter interval from the classic Cincinnatian (upper Katian, middle Maysvillian North American Stage) upper Fairview Formation, Miamitown Shale, and lower Grant Lake formations at four localities near Cincinnati, Ohio. For each of approximately 50 distinguishable limestone depositional units in each locality, a 2 × 2 cm square was selected for study. Each square was assigned a textural classification (mud content of intergranular space) and a breakage rank (pristine to comminuted). Phosphatic particle distribution was quantified both by visual estimation and by particle counting, with counts ranging from none detected to over 1000 per 4 cm2. Our analyses show a strong positive relationship between phosphate content and both textural maturity and fragmentation. This positive relationship is consistent with the PPC model and confirms that textural maturity can reflect the degree of condensation as well as depth-related environmental energy. This finding suggests that shell bed processes of repeated deposition and reworking make a significant contribution to the generation and accumulation of phosphatic particles. If local-scale sedimentary processes and conditions can control this accumulation, temporal changes in phosphatic sediment deposition rates may be linked to earth changes more complexly than through changing ocean chemistry on a global scale

ComSin: database of protein structures in bound (complex) and unbound (single) states in relation to their intrinsic disorder

Most of the proteins in a cell assemble into complexes to carry out their function. In this work, we have created a new database (named ComSin) of protein structures in bound (complex) and unbound (single) states to provide a researcher with exhaustive information on structures of the same or homologous proteins in bound and unbound states. From the complete Protein Data Bank (PDB), we selected 24 910 pairs of protein structures in bound and unbound states, and identified regions of intrinsic disorder. For 2448 pairs, the proteins in bound and unbound states are identical, while 7129 pairs have sequence identity 90% or larger. The developed server enables one to search for proteins in bound and unbound states with several options including sequence similarity between the corresponding proteins in bound and unbound states, and validation of interaction interfaces of protein complexes. Besides that, through our web server, one can obtain necessary information for studying disorder-to-order and order-to-disorder transitions upon complex formation, and analyze structural differences between proteins in bound and unbound states. The database is available at http://antares.protres.ru/comsin/

Spin-Resolved Topology and Partial Axion Angles in Three-Dimensional Insulators

Topological insulating (TI) phases were originally highlighted for their disorder-robust bulk responses, such as the quantized Hall conductivity of 2D Chern insulators. With the discovery of time-reversal- ($\mathcal{T}$-) invariant 2D TIs, and the recognition that their spin Hall conductivity is generically non-quantized, focus has since shifted to boundary states as signatures of 2D and 3D TIs and symmetry-enforced topological crystalline insulators (TCIs). However, in $\mathcal{T}$-invariant (helical) 3D TCIs such as bismuth, $\alpha$-BiBr, and MoTe$_2$-termed higher-order TCIs (HOTIs)-the boundary signatures manifest as 1D hinge states, whose configurations are dependent on sample details, and bulk signatures remain unknown. In this work, we introduce nested spin-resolved Wilson loops and layer constructions as tools to characterize the bulk topological properties of spinful 3D insulators. We discover that helical HOTIs realize one of three spin-resolved phases with distinct responses that are quantitatively robust to large deformations of the bulk spin-orbital texture: 3D quantum spin Hall insulators (QSHIs), "spin-Weyl" semimetal states with gapless spin spectra, and $\mathcal{T}$-doubled axion insulator (T-DAXI) states with nontrivial partial axion angles $\theta^\pm = \pi$ indicative of a 3D spin-magnetoelectric bulk response. We provide experimental signatures of each spin-stable regime of helical HOTIs, including an extensive bulk spin Hall response in 3D QSHIs and half-quantized 2D TI states on the gapped surfaces of T-DAXIs originating from a partial parity anomaly. We use ab-initio calculations to compute the spin-resolved topology of candidate helical HOTIs, finding that $\beta$-MoTe$_2$ realizes a spin-Weyl state and that $\alpha$-BiBr hosts both 3D QSHI and T-DAXI regimes.Comment: v2: 19+141 pages, 8+44 figures. Expanded materials analysis, added detailed calculations of spin-resolved topology and spin Hall conductivity with applications to BiBr. 1 author added for help with additional analyses. Nested and spin-resolved Wilson loop code with example scripts and documentation freely available at https://github.com/kuansenlin/nested_and_spin_resolved_Wilson_loo

Report of the Topical Group on Cosmic Frontier 5 Dark Energy and Cosmic Acceleration: Cosmic Dawn and Before for Snowmass 2021

This report summarizes the envisioned research activities as gathered from the Snowmass 2021 CF5 working group concerning Dark Energy and Cosmic Acceleration: Cosmic Dawn and Before. The scientific goals are to study inflation and to search for new physics through precision measurements of relic radiation from the early universe. The envisioned research activities for this decade (2025-35) are constructing and operating major facilities and developing critical enabling capabilities. The major facilities for this decade are the CMB-S4 project, a new Stage-V spectroscopic survey facility, and existing gravitational wave observatories. Enabling capabilities include aligning and investing in theory, computation and model building, and investing in new technologies needed for early universe studies in the following decade (2035+).Comment: contribution to Snowmass 202