The Complex Portal (www.ebi.ac.uk/complexportal) is a manually curated, encyclopaedic database that collates and summarizes information on stable, macromolecular complexes of known function. It captures complex composition, topology and function and links out to a large range of domain-specific resources that hold more detailed data, such as PDB or Reactome. We have made several significant improvements since our last update, including improving compliance to the FAIR data principles by providing complex-specific, stable identifiers that include versioning. Protein complexes are now available from 20 species for download in standards-compliant formats such as PSI-XML, MI-JSON and ComplexTAB or can be accessed via an improved REST API. A component-based JS front-end framework has been implemented to drive a new website and this has allowed the use of APIs from linked services to import and visualize information such as the 3D structure of protein complexes, its role in reactions and pathways and the co-expression of complex components in the tissues of multi-cellular organisms. A first draft of the complete complexome of Saccharomyces cerevisiae is now available to browse and download.

Hepatocellular organic anion transporting polypeptides (OATP1B1, OATP1B3, and OATP2B1) are important for proper liver function and the regulation of the drug elimination process. Understanding their roles in different conditions of liver toxicity and cancer requires an in-depth investigation of hepatic OATP–ligand interactions and selectivity. However, such studies are impeded by the lack of crystal structures, the promiscuous nature of these transporters, and the limited availability of reliable bioactivity data, which are spread over different data sources in the open domain. To this end, we integrated ligand bioactivity data for hepatic OATPs from five open data sources (ChEMBL, the UCSF–FDA TransPortal database, DrugBank, Metrabase, and IUPHAR) in a semiautomatic KNIME workflow. Highly curated data sets were analyzed with respect to enriched scaffolds, and their activity profiles and interesting scaffold series providing indication for selective, dual-, or pan-inhibitory activity toward hepatic OATPs could be extracted. In addition, a sequential binary modeling approach revealed common and distinctive ligand features for inhibitory activity toward the individual transporters. The workflows designed for integrating data from open sources, data curation, and subsequent substructure analyses are freely available and fully adaptable. The new data sets for inhibitors and substrates of hepatic OATPs as well as the insights provided by the feature and substructure analyses will guide future structure-based studies on hepatic OATP–ligand interactions and selectivity.

Organic anion and cation transporting proteins (OATs, OATPs, and OCTs), as well as the Multidrug and Toxin Extrusion (MATE) transporters of the Solute Carrier (SLC) family are playing a pivotal role in the discovery and development of new drugs due to their involvement in drug disposition, drug-drug interactions, adverse drug effects and related toxicity. Computational methods to understand and predict clinically relevant transporter interactions can provide useful guidance at early stages in drug discovery and design, especially if they include contemporary data science approaches. In this review, we summarize the current state-of-the-art of computational approaches for exploring ligand interactions and selectivity for these drug (uptake) transporters. The computational methods discussed here by highlighting interesting examples from the current literature are ranging from semiautomatic data mining and integration, to ligand-based methods (such as quantitative structure-activity relationships, and combinatorial pharmacophore modeling), and finally structure-based methods (such as comparative modeling, molecular docking, and molecular dynamics simulations). We are focusing on promising computational techniques such as fold-recognition methods, proteochemometric modeling or techniques for enhanced sampling of protein conformations used in the context of these ADMET-relevant SLC transporters with a special focus on methods useful for studying ligand selectivity.

Antimicrobial peptides (AMPs) can kill pathogens via the formation of permeable 14 membrane pores. However, matching peptide properties with their ability to form pores remains 15 elusive. In particular, the proline/glycine kink in helical AMPs was reported to both increase and 16 decrease antimicrobial activity. We used computer simulations and fluorescence leakage 17 experiments to show that a kink in helices affects the formation of membrane pores by stabilizing 18 toroidal pores but disrupting barrel-stave pores. The precise position of the proline/glycine kink in 19 the sequence further controls the formation of specific toroidal pore structure: U-or 20 hourglass-shaped. Moreover, we demonstrate that two helical peptides can form a stable kink-like 21 connection with similar behavior as one long helical peptide with kink. The provided 22 molecular-level insight can be utilized for rational design or modification of antibacterial peptides 23 or toxins to alter their ability to form membrane pores. 24 25 36AMPs possess an amphiphilic character with a sequence composed of both hydrophobic and 37 hydrophilic residues arranged in discrete clusters. (8) Such a distribution is thought to be the key 38 factor for binding to the pathogen's membrane and its disruption, while a common positive net 39 charge is responsible for the increased selectivity towards bacterial cells. (9; 10) AMPs are typically 40 1 of 29 Manuscript submitted to eLife unstructured in solution and frequently adopt an -helical conformation upon interaction with 41 the membrane. Their sequence can contain proline or glycine residues, which cause perturbation 42 in the regular -helical pattern. As a result, a substantial number of the known AMPs has been 43 determined to possess a helix-kink-helix motif. (11) The presence of a helical kink has been shown 44 to be biologically relevant or even responsible for the AMP's activity. (12; 13) However, the effect of 45 the kink on antimicrobial activity has been the subject of controversy over the past few decades. 46 Methodologically diverse studies have produced contradictory results, reporting the helical kink to 47 53 features of various peptides (Magainin II (30), LL-37 (31), Buforin II (32), -lysin (33), Candidalysin (34), 54 and their mutants) with their effect on pore stability. We found that the presence of a kink disrupts 55 barrel-stave, but stabilizes toroidal pores. Moreover, the position of the proline/glycine kink with 56 respect to the hydrophobic patch on AMP determined the peptide arrangement within the toroidal 57 pore. The pore formation of various mutants was further verified using a fluorescence leakage 58 assay on large unilamellar vesicles (LUVs). 59 Results and Discussion60 Contradictory Effect of -helical Kink on Barrel-stave Pore and Toroidal Pore Mech-61 anism 62Firstly, we investigated the effect of general peptide properties on the formation of a barrel-stave 63 pore (BP) and toroidal pore (TP) using MC simulations with phenomenological models (28) (see 64 Figu...