MOTIVATION: High-throughput DNA sequencing has revealed millions of single nucleotide variants (SNVs) in the human genome, with a small fraction linked to disease. The effect of missense variants, which alter the protein sequence, is particularly challenging to interpret due to the scarcity of clinical annotations and experimental information. While using conservation and structural information, current prediction tools still struggle to predict variant pathogenicity. In this study, we explored the pathogenicity of homologous missense variants-variants in equivalent positions across homologous proteins-focusing on proteins involved in autosomal dominant diseases. RESULTS: Our analysis of 2976 pathogenic and 17 555 non-pathogenic homologous variants demonstrated that pathogenicity can be extrapolated with 95% accuracy within a family, or up to 98% for closer homologs. Remarkably, the evaluation of 27 commonly used mutation predictor methods revealed that they were not fully capturing this biological feature. To facilitate the exploration of homologous variants, we created HomolVar, a web server that computationally predicts the pathogenesis of missense variants using annotations from homologous variants, freely available at https://rarevariants.org/HomolVar. Overall, these findings and the accompanying tool offer a robust method for predicting the pathogenicity of unannotated variants, enhancing genotype-phenotype correlations, and contributing to diagnosing rare genetic disorders. AVAILABILITY AND IMPLEMENTATION: HomolVar is freely available at https://rarevariants.org/HomolVar.

MOTIVATION: G protein-coupled receptors (GPCRs) can form homo-, heterodimers and larger order oligomers that exert different functions than monomers. The pharmacological potential of such complexes is hampered by the limited information available on the type of complex formed and its quaternary structure. Several GPCR structures in the Protein Data Bank display crystallographic interfaces potentially compatible with physiological interactions. RESULTS: Here, we present DIMERBOW, a database and web application aimed to visually browse the complete repertoire of potential GPCR dimers present in solved structures. The tool is suited to help finding the best possible structural template to model GPCR homomers. AVAILABILITY AND IMPLEMENTATION: DIMERBOW is available at http://lmc.uab.es/dimerbow/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: The number of available membrane protein structures has markedly increased in the last years and, in parallel, the reliability of the methods to detect transmembrane (TM) segments. In the present report, we characterized inter-residue interactions in α-helical membrane proteins using a dataset of 3462 TM helices from 430 proteins. This is by far the largest analysis published to date. RESULTS: Our analysis of residue-residue interactions in TM segments of membrane proteins shows that almost all interactions involve aliphatic residues and Phe. There is lack of polar-polar, polar-charged and charged-charged interactions except for those between Thr or Ser sidechains and the backbone carbonyl of aliphatic and Phe residues. The results are discussed in the context of the preferences of amino acids to be in the protein core or exposed to the lipid bilayer and to occupy specific positions along the TM segment. Comparison to datasets of β-barrel membrane proteins and of α-helical globular proteins unveils the specific patterns of interactions and residue composition characteristic of α-helical membrane proteins that are the clue to understanding their structure. AVAILABILITY AND IMPLEMENTATION: Results data and datasets used are available at http://lmc.uab.cat/TMalphaDB/interactions.php. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Membrane proteins represent over 25 % of human protein genes and account for more than 60 % of drug targets due to their accessibility from the extracellular environment. The increasing number of available crystal structures of these proteins in the Protein Data Bank permits an initial estimation of their structural properties. DESCRIPTION: We have developed two web servers-TMalphaDB for α-helix bundles and TMbetaDB for β-barrels-to analyse the growing repertoire of available crystal structures of membrane proteins. TMalphaDB and TMbetaDB permit to search for these specific sequence motifs in a non-redundant structure database of transmembrane segments and quantify structural parameters such as ϕ and ψ backbone dihedral angles, χ1 side chain torsion angle, unit bend and unit twist. CONCLUSIONS: The structural information offered by TMalphaDB and TMbetaDB permits to quantify structural distortions induced by specific sequence motifs, and to elucidate their role in the 3D structure. This specific structural information has direct implications in homology modeling of the growing sequences of membrane proteins lacking experimental structure. TMalphaDB and TMbetaDB are freely available at http://lmc.uab.cat/TMalphaDB and http://lmc.uab.cat/TMbetaDB.

MOTIVATION: Integral polytopic membrane proteins contain only two types of folds in their transmembrane domains: α-helix bundles and β-barrels. The increasing number of available crystal structures of these proteins permits an initial estimation of how sequence variability affects the structure conservation in their transmembrane domains. We, thus, aim to determine the pairwise sequence identity necessary to maintain the transmembrane molecular architectures compatible with the hydrophobic nature of the lipid bilayer. RESULTS: Root-mean-square deviation (rmsd) and sequence identity were calculated from the structural alignments of pairs of homologous polytopic membrane proteins sharing the same fold. Analysis of these data reveals that transmembrane segment pairs with sequence identity in the so-called 'twilight zone' (20-35%) display high-structural similarity (rmsd < 1.5 Å). Moreover, a large group of β-barrel pairs with low-sequence identity (<20%) still maintain a close structural similarity (rmsd < 2.5 Å). Thus, we conclude that fold preservation in transmembrane regions requires less sequence conservation than for globular proteins. These findings have direct implications in homology modeling of evolutionary-related membrane proteins. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.