3D-Fun: predicting enzyme function from structure

The ‘omics’ revolution is causing a flurry of data that all needs to be annotated for it to become useful. Sequences of proteins of unknown function can be annotated with a putative function by comparing them with proteins of known function. This form of annotation is typically performed with BLAST or similar software. Structural genomics is nowadays also bringing us three dimensional structures of proteins with unknown function. We present here software that can be used when sequence comparisons fail to determine the function of a protein with known structure but unknown function. The software, called 3D-Fun, is implemented as a server that runs at several European institutes and is freely available for everybody at all these sites. The 3D-Fun servers accept protein coordinates in the standard PDB format and compare them with all known protein structures by 3D structural superposition using the 3D-Hit software. If structural hits are found with proteins with known function, these are listed together with their function and some vital comparison statistics. This is conceptually very similar in 3D to what BLAST does in 1D. Additionally, the superposition results are displayed using interactive graphics facilities. Currently, the 3D-Fun system only predicts enzyme function but an expanded version with Gene Ontology predictions will be available soon. The server can be accessed at http://3dfun.bioinfo.pl/ or at http://3dfun.cmbi.ru.nl/

De delirii trementis natura : dissertatio inauguralis medica

http://tartu.ester.ee/record=b1932282~S1*es

PDB-UF: Database of Predicted Enzymatic Functions for Unannotated Protein Structures from Structural Genomics

The number of protein structures from structural genomics centers dramatically increases in the Protein Data Bank (PDB). Many of these structures are functionally unannotated because they have no sequence similarity to proteins of known function. However, it is possible to successfully infer function using only structural similarity. Here we present the PDB-UF database, a web-accessible collection of predictions of enzymatic properties using structure-function relationship. The assignments were conducted for three-dimensional protein structures of unknown function that come from structural genomics initiatives. We show that 4 hypothetical proteins (with PDB accession codes: 1VH0, 1NS5, 1O6D, and 1TO0), for which standard BLAST tools such as PSI-BLAST or RPS-BLAST failed to assign any function, are probably methyltransferase enzymes. We suggest that the structure-based prediction of an EC number should be conducted having the different similarity score cutoff for different protein folds. Moreover, performing the annotation using two different algorithms can reduce the rate of false positive assignments. We believe, that the presented web-based repository will help to decrease the number of protein structures that have functions marked as "unknown" in the PDB file.Chemistry and Chemical Biolog

Principles of genome evolution in the Drosophila melanogaster species group.

That closely related species often differ by chromosomal inversions was discovered by Sturtevant and Plunkett in 1926. Our knowledge of how these inversions originate is still very limited, although a prevailing view is that they are facilitated by ectopic recombination events between inverted repetitive sequences. The availability of genome sequences of related species now allows us to study in detail the mechanisms that generate interspecific inversions. We have analyzed the breakpoint regions of the 29 inversions that differentiate the chromosomes of Drosophila melanogaster and two closely related species, D. simulans and D. yakuba, and reconstructed the molecular events that underlie their origin. Experimental and computational analysis revealed that the breakpoint regions of 59% of the inversions (17/29) are associated with inverted duplications of genes or other nonrepetitive sequences. In only two cases do we find evidence for inverted repetitive sequences in inversion breakpoints. We propose that the presence of inverted duplications associated with inversion breakpoint regions is the result of staggered breaks, either isochromatid or chromatid, and that this, rather than ectopic exchange between inverted repetitive sequences, is the prevalent mechanism for the generation of inversions in the melanogaster species group. Outgroup analysis also revealed evidence for widespread breakpoint recycling. Lastly, we have found that expression domains in D. melanogaster may be disrupted in D. yakuba, bringing into question their potential adaptive significance

Hydrogen Dynamics in Superprotonic CsHSO4

We present a detailed study of proton dynamics in the hydrogen-bonded superprotonic conductor CsHSO4 from first-principles molecular dynamics simulations, isolating the subtle interplay between the dynamics of the O--H chemical bonds, the O...H hydrogen bonds, and the SO4 tetrahedra in promoting proton diffusion. We find that the Grotthus mechanism of proton transport is primarily responsible for the dynamics of the chemical bonds, whereas the reorganization of the hydrogen-bond network is dominated by rapid angular hops in concert with small reorientations of the SO4 tetrahedra. Frequent proton jumping across the O--H...O complex is countered by a high rate of jump reversal, which we show is connected to the dynamics of the SO4 tetrahedra, resulting in a diminished CsHSO4/CsDSO4 isotope effect. We also find evidence of multiple timescales for SO4 reorientation events, leading to distinct diffusion mechanisms along the different crystal lattice directions. Finally, we employ graph-theoretic techniques to characterize the topology of the hydrogen-bond network and demonstrate a clear relationship between certain connectivity configurations and the likelihood for diffusive jump events.Comment: 12 pages, 10 figure

Finding Cures for Tropical Diseases: Is Open Source an Answer?

The Tropical Disease Initiative will be a Web-based, community- wide effort where scientists from the public and private sectors join together to discover new treatment

A novel method for comparing topological models of protein structures enhanced with ligand information

This article is available open access through the publisher’s website through the link below. Copyright @ 2008 The Authors.We introduce TOPS+ strings, a highly abstract string-based model of protein topology that permits efficient computation of structure comparison, and can optionally represent ligand information. In this model, we consider loops as secondary structure elements (SSEs) as well as helices and strands; in addition we represent ligands as first class objects. Interactions between SSEs and between SSEs and ligands are described by incoming/outgoing arcs and ligand arcs, respectively; and SSEs are annotated with arc interaction direction and type. We are able to abstract away from the ligands themselves, to give a model characterized by a regular grammar rather than the context sensitive grammar of the original TOPS model. Our TOPS+ strings model is sufficiently descriptive to obtain biologically meaningful results and has the advantage of permitting fast string-based structure matching and comparison as well as avoiding issues of Non-deterministic Polynomial time (NP)-completeness associated with graph problems. Our structure comparison method is computationally more efficient in identifying distantly related proteins than BLAST, CLUSTALW, SSAP and TOPS because of the compact and abstract string-based representation of protein structure which records both topological and biochemical information including the functionally important loop regions of the protein structures. The accuracy of our comparison method is comparable with that of TOPS. Also, we have demonstrated that our TOPS+ strings method out-performs the TOPS method for the ligand-dependent protein structures and provides biologically meaningful results. Availability: The TOPS+ strings comparison server is available from http://balabio.dcs.gla.ac.uk/mallika/WebTOPS/topsplus.html.University of Glasgo

Comprehensive genomic analyses associate UGT8 variants with musical ability in a Mongolian population

Background: Musical abilities such as recognising music and singing performance serve as means for communication and are instruments in sexual selection. Specific regions of the brain have been found to be activated by musical stimuli, but these have rarely been extended to the discovery of genes and molecules associated with musical ability. Methods: A total of 1008 individuals from 73 families were enrolled and a pitch-production accuracy test was applied to determine musical ability. To identify genetic loci and variants that contribute to musical ability, we conducted family-based linkage and association analyses, and incorporated the results with data from exome sequencing and array comparative genomic hybridisation analyses. Results: We found significant evidence of linkage at 4q23 with the nearest marker D4S2986 (LOD=3.1), whose supporting interval overlaps a previous study in Finnish families, and identified an intergenic single nucleotide polymorphism (SNP) $(rs1251078, p=8.4×10^{−17})$ near UGT8, a gene highly expressed in the central nervous system and known to act in brain organisation. In addition, a non-synonymous SNP in UGT8 was revealed to be highly associated with musical ability $(rs4148254, p=8.0×10^{−17})$, and a 6.2 kb copy number loss near UGT8 showed a plausible association with musical ability $(p=2.9×10^{−6})$. Conclusions: This study provides new insight into the genetics of musical ability, exemplifying a methodology to assign functional significance to synonymous and non-coding alleles by integrating multiple experimental methods