MOTIVATION: Effective use of evolutionary information has recently led to tremendous progress in computational prediction of three-dimensional (3D) structures of proteins and their complexes. Despite the progress, the accuracy of predicted structures tends to vary considerably from case to case. Since the utility of computational models depends on their accuracy, reliable estimates of deviation between predicted and native structures are of utmost importance. RESULTS: For the first time, we present a deep convolutional neural network (CNN) constructed on a Voronoi tessellation of 3D molecular structures. Despite the irregular data domain, our data representation allows us to efficiently introduce both convolution and pooling operations and train the network in an end-to-end fashion without precomputed descriptors. The resultant model, VoroCNN, predicts local qualities of 3D protein folds. The prediction results are competitive to state of the art and superior to the previous 3D CNN architectures built for the same task. We also discuss practical applications of VoroCNN, for example, in recognition of protein binding interfaces. AVAILABILITY AND IMPLEMENTATION: The model, data and evaluation tests are available at https://team.inria.fr/nano-d/software/vorocnn/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: VoroContacts is a versatile tool for computing and analyzing contact surface areas (CSAs) and solvent accessible surface areas (SASAs) for three-dimensional (3D) structures of proteins, nucleic acids and their complexes at the atomic resolution. CSAs and SASAs are derived using Voronoi tessellation of 3D structure, represented as a collection of atomic balls. VoroContacts web server features a highly configurable query interface, which enables on-the-fly analysis of contacts for selected set of atoms and allows filtering interatomic contacts by their type, surface areas, distance between contacting atoms and sequence separation between contacting residues. The VoroContacts functionality is also implemented as part of the standalone Voronota package, enabling batch processing. AVAILABILITY AND IMPLEMENTATION: https://bioinformatics.lt/wtsam/vorocontacts. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Measuring discrepancies between protein models and native structures is at the heart of development of protein structure prediction methods and comparison of their performance. A number of different evaluation methods have been developed; however, their comprehensive and unbiased comparison has not been performed. RESULTS: We carried out a comparative analysis of several popular model assessment methods (RMSD, TM-score, GDT, QCS, CAD-score, LDDT, SphereGrinder and RPF) to reveal their relative strengths and weaknesses. The analysis, performed on a large and diverse model set derived in the course of three latest community-wide CASP experiments (CASP10-12), had two major directions. First, we looked at general differences between the scores by analyzing distribution, correspondence and correlation of their values as well as differences in selecting best models. Second, we examined the score differences taking into account various structural properties of models (stereochemistry, hydrogen bonds, packing of domains and chain fragments, missing residues, protein length and secondary structure). Our results provide a solid basis for an informed selection of the most appropriate score or combination of scores depending on the task at hand. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Summary: The PPI3D web server is focused on searching and analyzing the structural data on protein-protein interactions. Reducing the data redundancy by clustering and analyzing the properties of interaction interfaces using Voronoi tessellation makes this software a highly effective tool for addressing different questions related to protein interactions. Availability and Implementation: The server is freely accessible at http://bioinformatics.lt/software/ppi3d/ . Contact: [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

Background The ability to replicate is essential for all living entities. Duplication of genetic information is carried out by replication proteins. DNA replication has been well studied in T7, T4 phages and herpes viruses; however, the information about replication mechanisms from other groups of viruses is either scarce or missing altogether. Double-stranded (ds) DNA viruses infect cells from all domains of life, they evolve fast and are very diverse. Their genome size varies from 5 to 2,500 kbp.

MOTIVATION: Herpesviruses are large DNA viruses causing a variety of diseases in humans and animals. To develop effective treatment, it is important to understand the mechanisms of their replication. One of the components of the herpesviral DNA replication system is a helicase-primase complex, consisting of UL5 (helicase), UL52 (primase) and UL8. UL8 is an essential herpesviral protein involved in multiple protein-protein interactions. Intriguingly, so far no UL8 homologs outside of herpesviruses could be identified. Moreover, nothing is known about its structure or domain organization. RESULTS: Here, combining sensitive homology detection methods and homology modeling, we found that the UL8 protein family is related to B-family polymerases. In the course of evolution, UL8 has lost the active site and has undergone a reduction of DNA-binding motifs. The loss of active site residues explains the failure to detect any catalytic activity of UL8. A structural model of human herpes virus 1 UL8 constructed as part of the study is consistent with the mutation data targeting its interaction with primase UL52. It also provides a platform for studying multiple interactions that UL8 is involved in. The two other components of helicase-primase complex show evolutionary links with a newly characterized human primase that also has DNA polymerase activity (PrimPol) and the Pif1 helicase, respectively. The role of these enzymes in recovering stalled replication forks suggests mechanistic and functional similarities with herpesviral proteins. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Eukaryote-infecting nucleo-cytoplasmic large DNA viruses (NCLDVs) feature some of the largest genomes in the viral world. These viruses typically do not strongly depend on the host DNA replication systems. In line with this observation, a number of essential DNA replication proteins, such as DNA polymerases, primases, helicases and ligases, have been identified in the NCLDVs. One other ubiquitous component of DNA replisomes is the single-stranded DNA-binding (SSB) protein. Intriguingly, no NCLDV homologs of canonical OB-fold-containing SSB proteins had previously been detected. Only in poxviruses, one of seven NCLDV families, I3 was identified as the SSB protein. However, whether I3 is related to any known protein structure has not yet been established. RESULTS: Here, we addressed the case of 'missing' canonical SSB proteins in the NCLDVs and also probed evolutionary origins of the I3 family. Using advanced computational methods, in four NCLDV families, we detected homologs of the bacteriophage T7 SSB protein (gp2.5). We found the properties of these homologs to be consistent with the SSB function. Moreover, we implicated specific residues in single-stranded DNA binding. At the same time, we found no evolutionary link between the T7 gp2.5-like NCLDV SSB homologs and the poxviral SSB protein (I3). Instead, we identified a distant relationship between I3 and small protein B (SmpB), a bacterial RNA-binding protein. Thus, apparently, the NCLDVs have the two major distinct sets of SSB proteins having bacteriophage and bacterial origins, respectively.

UNLABELLED: We present Voroprot, an interactive cross-platform software tool that provides a unique set of capabilities for exploring geometric features of protein structure. Voroprot allows the construction and visualization of the Apollonius diagram (also known as the additively weighted Voronoi diagram), the Apollonius graph, protein alpha shapes, interatomic contact surfaces, solvent accessible surfaces, pockets and cavities inside protein structure. AVAILABILITY: Voroprot is available for Windows, Linux and Mac OS X operating systems and can be downloaded from http://www.ibt.lt/bioinformatics/voroprot/.

SUMMARY: Detection of distant homology is a widely used computational approach for studying protein evolution, structure and function. Here, we report a homology search web server based on sequence profile-profile comparison. The user may perform searches in one of several regularly updated profile databases using either a single sequence or a multiple sequence alignment as an input. The same profile databases can also be downloaded for local use. The capabilities of the server are illustrated with the identification of new members of the highly diverse PD-(D/E)XK nuclease superfamily. AVAILABILITY: http://www.ibt.lt/bioinformatics/coma/

BACKGROUND: Detection of common evolutionary origin (homology) is a primary means of inferring protein structure and function. At present, comparison of protein families represented as sequence profiles is arguably the most effective homology detection strategy. However, finding the best way to represent evolutionary information of a protein sequence family in the profile, to compare profiles and to estimate the biological significance of such comparisons, remains an active area of research. RESULTS: Here, we present a new homology detection method based on sequence profile-profile comparison. The method has a number of new features including position-dependent gap penalties and a global score system. Position-dependent gap penalties provide a more biologically relevant way to represent and align protein families as sequence profiles. The global score system enables an analytical solution of the statistical parameters needed to estimate the statistical significance of profile-profile similarities. The new method, together with other state-of-the-art profile-based methods (HHsearch, COMPASS and PSI-BLAST), is benchmarked in all-against-all comparison of a challenging set of SCOP domains that share at most 20% sequence identity. For benchmarking, we use a reference ("gold standard") free model-based evaluation framework. Evaluation results show that at the level of protein domains our method compares favorably to all other tested methods. We also provide examples of the new method outperforming structure-based similarity detection and alignment. The implementation of the new method both as a standalone software package and as a web server is available at http://www.ibt.lt/bioinformatics/coma. CONCLUSION: Due to a number of developments, the new profile-profile comparison method shows an improved ability to match distantly related protein domains. Therefore, the method should be useful for annotation and homology modeling of uncharacterized proteins.

BACKGROUND: Sequence searches are routinely employed to detect and annotate related proteins. However, a rapid growth of databases necessitates a frequent repetition of sequence searches and subsequent analysis of obtained results. Although there are several automatic systems available for executing periodical sequence searches and reporting results, they all suffer either from a lack of sensitivity, restrictive database choice or limited flexibility in setting up search strategies. Here, a new sequence search and reporting software package designed to address these shortcomings is described. RESULTS: Re-searcher is an open-source highly configurable system for recurrent detection and reporting of new homologs for the sequence of interest in specified protein sequence databases. Searches are performed using PSI-BLAST at desired time intervals either within NCBI or local databases. In addition to searches against individual databases, the system can perform "PDB-BLAST"-like combined searches, when PSI-BLAST profile generated during search against the first database is used to search the second database. The system supports multiple users enabling each to separately keep track of multiple queries and query-specific results. CONCLUSIONS: Re-searcher features a large number of options enabling automatic periodic detection of both close and distant homologs. At the same time it has a simple and intuitive interface, making the analysis of results even for a large number of queries a straightforward task.

BACKGROUND: Protein sequence alignments have become indispensable for virtually any evolutionary, structural or functional study involving proteins. Modern sequence search and comparison methods combined with rapidly increasing sequence data often can reliably match even distantly related proteins that share little sequence similarity. However, even highly significant matches generally may have incorrectly aligned regions. Therefore when exact residue correspondence is used to transfer biological information from one aligned sequence to another, it is critical to know which alignment regions are reliable and which may contain alignment errors. RESULTS: PSI-BLAST-ISS is a standalone Unix-based tool designed to delineate reliable regions of sequence alignments as well as to suggest potential variants in unreliable regions. The region-specific reliability is assessed by producing multiple sequence alignments in different sequence contexts followed by the analysis of the consistency of alignment variants. The PSI-BLAST-ISS output enables the user to simultaneously analyze alignment reliability between query and multiple homologous sequences. In addition, PSI-BLAST-ISS can be used to detect distantly related homologous proteins. The software is freely available at: http://www.ibt.lt/bioinformatics/iss. CONCLUSION: PSI-BLAST-ISS is an effective reliability assessment tool that can be useful in applications such as comparative modelling or analysis of individual sequence regions. It favorably compares with the existing similar software both in the performance and functional features.