Genome-wide survey of remote homologues for protein domain superfamilies of known. structure reveals unequal distribution across structural classes

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1 Electronic Supplementary Material (ESI) for Molecular Omics. This journal is The Royal Society of Chemistry 2018 Genome-wide survey of remote homologues for protein superfamilies of known structure reveals unequal distribution across structural classes Meenakshi S. Iyer, Adwait Joshi and Ramanathan Sowdhamini* Supplementary Figure 1: The work-flow followed in the paper has been illustrated. Each hit identified by sequence searches undergoes the following steps- validation using superfamily HMMs, DA determination at SCOP and Pfam level, finding the taxonomic occurrence.

2 a) Rotavirus A, Rotavirus C and Equine Encephalovirus b) Metazoa c) Plants and oomycete plant pathogens d) Eubacteria Eubacteria e) Eubacteria Eubacteria and Viridiplantae Supplementary Figure 2: The phylogenetic trees obtained using the DA for the superfamilies a) (red) b) (green) c) (blue) d) (purple) e) (orange) are shown. We see that that similar DA like repeats (51101) and same pair of s associated with other s (55239 and 51161) are clustered and unrelated s are well-separated. The taxonomic distribution of the different DA is indicated.

3 Supplementary Table 1: The HMM library was created using all the PASS2.4 member sequences and the superfamily alignments. PASS2.4 is divided into different categories based on the number of PASS2.4 members in the superfamily into Single-membered (SMS), Two-membered (TMS) and multi-membered superfamilies (MMS). PASS2.4 also provides structure-based sequence alignments for all the superfamilies. Since, SMS have only a single member, the SF-HMM is a single sequence HMM. There were in total 1080 SF-HMMs and SQ-HMMs, total HMMs. We used the superfamily alignments and the member sequences to create a HMM library with a total of 11,749 HMMs. SF-HMM PASS2.4 superfamily alignment HMM, SQ-HMM Single query HMM. Type of HMM Number of SMS Number of TMS Number of MMS Total library HMM HMM HMM SF-HMM SQ-HMM ,569 Total ,749

4 Supplementary Table 2: Number of sequence search (PHI-BLAST and CS-BLAST) and validation (HMMSCAN) runs carried out in the study. Sequence search Number of runs Number of runs Number of runs Total method in SMS in TMS in MMS CS-BLAST ,970 10,566 PHI-BLAST 4,425 4,405 4,662 13,492 Total 5,289 5,137 13,632 24, 058 Sequence search method CS-BLAST HMM library Number of runs in SMS Number of runs in TMS Number of runs in MMS Total PASS ,940 HMM Pfam HMM ,940 PHI-BLAST PASS ,721 HMM Pfam HMM ,721 Total Total 3,066 1,402 2,854 7,322

5 Supplementary Table 3: The comparison of the MP and MQ approach for the superfamily test dataset. MQ approach picks up more hits whereas the MP approach has a better Positive Prediction Value (PPV). MP- Multi-Pattern, MQ- Multi-Query, TP- True Positive, FP- False positive SCOP Superfamily Superfamily description Total TP_total FP_total Total PPV MP_total MP_TP MP_FP MP PPV MQ_total MQ_TP MQ_FP MQ PPV ACP-like Insect Pheromone- OBPs A virus capsid protein alpha helical Bacterial Enterotoxins Carbonic anhydrase Mannosebinding lectins Triosephosphat e isomerase Bacterialluciferase like Nucleotidebinding Bacterial exopeptidase dimerisation RuBisCo-small subunit

6 Supplementary Table 4: The number of hits obtained for each superfamily using the different sequence search approaches has been provided with the taxonomic distribution. The SCOP class and fold code have also been provided. The numbers indicate the number of true positive hits for the different taxa. CLASS FOLD SF SUPERFAMILY DESCRIPTION CSBLAST HITS PHIBLAST HITS CSBLAST TP HITS PHIBLAST TP LIST PHIBLAST PDB COUNT CSBLAST PDB COUNT ALL PDB COUNT PFAM UNIQUE DA PASS2 UNIQUE DA TAXID CELLULAR ORGANISMS VIRUS UNCHARACTERISED ENVIRONMENTAL SAMPLE BACTERIA ARCHAEA PLANT METAZOA PROTEOBACTERIA ACTINOBACTERIA FIRMICUTES SAR FUNGI Globin-like alpha-helical ferredoxin GreA transcript cleavage protein, N-terminal Ribosomal protein L29 (L29p) Chaperone J DNA polymerase III theta subunit-like Prefoldin HR1 repeat trna-binding arm Eukaryotic DNA topoisomerase I, dispensable insert C-terminal UvrC-binding of UvrB Epsilon subunit of F1F0-ATP synthase C-terminal Fe,Mn superoxide dismutase (SOD), N-terminal Cytochrome c Homeo-like Methylated DNA-protein cysteine methyltransferase, C-terminal ARID-like Winged helix DNA-binding C-terminal effector of the bipartite response regulators Ribosomal protein L11, C-terminal Ribosomal protein S Polynucleotide phosphorylase/guanosine pentaphosphate synthase (PNPase/GPSI), N-terminal Zn binding of HIV integrase RNA polymerase subunit RPB DNA helicase RuvA subunit, C-terminal UBA-like CRAL/TRIO N-terminal Elongation factor TFIIS S13-like H2TH Double-stranded DNA-binding Putative DNA-binding Spectrin repeat Enzyme IIa from lactose specific PTS, IIa-lac Succinate dehydrogenase/fumarate reductase flavoprotein C-terminal Smac/diablo Tubulin chaperone cofactor A Ribosomal protein S Bacterial immunoglobulin/albumin-binding s Peripheral subunit-binding of 2-oxo acid dehydrogenase complex Protozoan pheromone proteins Acyl-CoA binding protein Second of FERM Kix of CBP (creb binding protein) RAP -like VHP, Villin headpiece TAF(II)230 TBP-binding fragment S15/NS1 RNA-binding Cysteine alpha-hairpin motif T4 endonuclease V Fertilization protein PGBD-like HMG-box Histone-fold HSC20 (HSCB), C-terminal oligomerisation Diol dehydratase, gamma subunit Methane monooxygenase hydrolase, gamma subunit Mitochondrial import receptor subunit Tom Apolipoprotein Aspartate receptor, ligand-binding Cytochromes Hemerythrin-like TMV-like viral coat proteins Acyl-CoA dehydrogenase C-terminal -like FKBP12-rapamycin-binding of FKBP-rapamycin-associated protein (FRAP) Proteasome activator alpha-catenin/vinculin-like Histidine-containing phosphotransfer, HPT Bacterial GAP Ferritin-like helical cytokines Anticodon-binding of a subclass of class I aminoacyl-trna synthetases ACP-like Colicin E immunity proteins Retrovirus capsid dimerization -like Domain of the SRP/SRP receptor G-proteins Bromo ROP protein Homodimeric of signal transducing histidine kinase Dimerization-anchoring of camp-dependent PK regulatory subunit Transcription factor IIA (TFIIA), alpha-helical Ectatomin subunits SinR repressor dimerisation -like lambda repressor-like DNA-binding s Signal peptide-binding A DNA-binding in eukaryotic transcription factors HLH, helix-loop-helix DNA-binding EF-hand Insect pheromone/odorant-binding proteins Cloroperoxidase Calponin-homology, CH Domain of poly(adp-ribose) polymerase SWIB/MDM Ribbon-helix-helix GST C-terminal -like Methionine synthase Nucleoside phosphorylase/phosphoribosyltransferase N-terminal STAT t-snare proteins N-terminal of cbl (N-cbl) Transferrin receptor-like dimerisation Conserved common to transcription factors TFIIS, elongin A, CRSP C-terminal of B transposition protein

7 Anaphylotoxins (complement system) Cytochrome c oxidase subunit h Bifunctional inhibitor/lipid-transfer protein/seed storage 2S albumin p53 tetramerization Domain of early E2A DNA-binding protein, ADDBP IHF-like DNA-binding proteins CO dehydrogenase ISP C- like Protein HNS-dependent expression A; HdeA Chemotaxis receptor methyltransferase CheR, N-terminal PAH SAM/Pointed RuvA 2-like C-terminal of RNA polymerase alpha subunit Rad51 N-terminal -like Barrier-to-autointegration factor, BAF DNA polymerase beta, N-terminal -like ' to 3' exonuclease, C-terminal sub HRDC-like lambda integrase-like, N-terminal Enzyme I of the PEP:sugar phosphotransferase system HPr-binding (sub) Retroviral matrix proteins Hepatitis B viral capsid (hbcag) Apolipophorin-III Saposin Bacteriocin AS Annexin Transducin (alpha subunit), insertion Wiscott-Aldrich syndrome protein, WASP, C-terminal C-terminal of alpha and beta subunits of F1 ATP synthase Ypt/Rab-GAP of gyp1p N-terminal of the delta subunit of the F1F0-ATP synthase ERP29 C -like Functional of the splicing factor Prp Retrovirus capsid protein, N-terminal core Cyclin-like Ribosomal protein S Iron-dependent repressor protein, dimerization DEATH GntR ligand-binding -like NusB-like post-aaa+ oligomerization -like N-terminal of DnaB helicase FliG Guanido kinase N-terminal Scaffolding protein gpd of bacteriophage procapsid Hemocyanin, N-terminal Di-copper centre-containing DBL homology (DH-) LigA subunit of an aromatic-ring-opening dioxygenase LigAB Methyl-coenzyme M reductase alpha and beta chain C-terminal Transcription factor STAT-4 N Regulator of G-protein signaling, RGS Carbamoyl phosphate synthetase, large subunit connection Heme-dependent peroxidases Ribosomal protein L19 (L19e) Influenza virus matrix protein M DNA-glycosylase An anticodon-binding of class I aminoacyl-trna synthetases R1 subunit of ribonucleotide reductase, N-terminal Cryptochrome/photolyase FAD-binding phosphogluconate dehydrogenase C-terminal -like Uteroglobin-like Six-hairpin glycosidases Seven-hairpin glycosidases Chondroitin AC/alginate lyase Terpenoid cyclases/protein prenyltransferases Citrate synthase Cytochrome P TrpR-like Ribosomal protein L7/12, oligomerisation (N-terminal) Class II MHC-associated invariant chain ectoplasmic trimerization Aldehyde ferredoxin oxidoreductase, C-terminal s Acid phosphatase/vanadium-dependent haloperoxidase DNA repair protein MutS, III Interferon-induced guanylate-binding protein 1 (GBP1), C-terminal A virus capsid protein alpha-helical GTPase activation, GAP Ras GEF ARM repeat Ankyrin repeat Sec Lipovitellin-phosvitin complex, superhelical Bacterial muramidases Protein prenylyltransferase protein TPR-like ENTH/VHS Cytochrome c oxidase subunit E Lipoxigenase gene 59 helicase assembly protein Tetracyclin repressor-like, C-terminal Nuclear receptor ligand-binding Phospholipase C/P1 nuclease Serum albumin-like L-aspartase-like Terpenoid synthases GroEL equatorial -like Chorismate mutase II Peridinin-chlorophyll protein Heme oxygenase-like Phospholipase A2, PLA Fungal elicitin Tetraspanin FinO-like Ribosomal protein L39e Methanol dehydrogenase subunit Transducin (heterotrimeric G protein), gamma chain Fe-only hydrogenase smaller subunit Moesin tail Proteinase A inhibitor IA Epsilon subunit of mitochondrial F1F0-ATP synthase Multiheme cytochromes Immunoglobulin Fibronectin type III PKD beta-galactosidase/glucuronidase Transglutaminase, two C-terminal s Cadherin-like Actinoxanthin-like Cu,Zn superoxide dismutase-like CBD9-like Clathrin adaptor appendage PapD-like Purple acid phosphatase, N-terminal Superoxide reductase-like

8 Invasin/intimin cell-adhesion fragments Diphtheria toxin, C-terminal Carbohydrate-binding Bacterial adhesins Alpha-macroglobulin receptor p53-like transcription factors Cytochrome f, large Second of Mu2 adaptin subunit (ap50) of ap2 adaptor Starch-binding -like Carboxypeptidase regulatory -like VHL Transthyretin (synonym: prealbumin) Cna protein B-type Aromatic compound dioxygenase HSP40/DnaJ peptide-binding alpha-amylase inhibitor tendamistat Cupredoxins C2 (Calcium/lipid-binding, CaLB) Periplasmic chaperone C PHL pollen allergen Rab geranylgeranyltransferase alpha-subunit, insert TRAF -like Neurophysin II gamma-crystallin-like Lipase/lipooxygenase (PLAT/LH2 ) PHM/PNGase F Group II dsdna viruses VP Calpain large subunit, middle ( III) HSP20-like chaperones Ecotin, trypsin inhibitor PEBP-like Galactose-binding -like Viral protein ENV polyprotein, receptor-binding Virus attachment protein globular TNF-like Spermadhesin, CUB Hyaluronate lyase-like, C-terminal Osmotin, thaumatin-like protein SMAD/FHA Soluble secreted chemokine inhibitor, VCCI Baculovirus p35 protein Concanavalin A-like lectins/glucanases Amine oxidase catalytic EV matrix protein gp ISP C-terminal of transcriptional repressors SH Myosin S1 fragment, N-terminal Electron transport accessory proteins Translation proteins SH3-like Cell growth inhibitor/plasmid maintenance toxic component DNA-binding of retroviral integrase GroES-like SacY-like RNA-binding PDZ -like N-terminal s of the minor coat protein g3p Sm-like ribonucleoproteins Ribosomal protein L Staphylococcal nuclease Bacterial enterotoxins TIMP-like Nucleic acid-binding proteins Inorganic pyrophosphatase MOP-like CheW-like PRC-barrel Cytokine Ricin B-like lectins Agglutinin STI-like Actin-crosslinking proteins FucI/AraA C-terminal -like Translation proteins EF-Tu/eEF-1alpha/eIF2-gamma C-terminal FMN-binding split barrel FMT C-terminal -like Trypsin-like serine proteases mu transposase, C-terminal N-terminal of alpha and beta subunits of F1 ATP synthase Alanine racemase C-terminal -like Acid proteases ValRS/IleRS/LeuRS editing Barwin-like endoglucanases ADC-like Ribosomal protein L25-like Core binding factor beta, CBF PH -like Transcription factor IIA (TFIIA), beta-barrel Herpes virus serine proteinase, assemblin PK beta-barrel -like XRCC4, N-terminal Lipocalins Avidin/streptavidin beta-barrel protease inhibitors D-aminopeptidase, middle and C-terminal s Cyclophilin-like Oncogene products Mannose 6-phosphate receptor Rap30/74 interaction s Hemopexin-like Tachylectin Sialidases Soluble quinoprotein glucose dehydrogenase Thermostable phytase (3-phytase) TolB, C-terminal Galactose oxidase, central YVTN repeat-like/quinoprotein amine dehydrogenase Nitrous oxide reductase, N-terminal WD40 repeat-like RCC1/BLIP-II Clathrin heavy-chain terminal Peptidase/esterase 'gauge' Quinoprotein alcohol dehydrogenase-like C-terminal (heme d1) of cytochrome cd1-nitrite reductase Glycosyl hydrolase WW Carbohydrate binding Head of nucleotide exchange factor GrpE Carbonic anhydrase Bacteriochlorophyll A protein Outer surface protein Vitelline membrane outer protein-i (VMO-I) delta-endotoxin (insectocide), middle

9 Mannose-binding lectins alpha-d-mannose-specific plant lectins beta-roll Pectin lyase-like Insect cysteine-rich antifreeze protein Trimeric LpxA-like enzymes An insect antifreeze protein RmlC-like cupins Clavaminate synthase-like camp-binding -like Regulatory protein AraC TRAP-like Fibre shaft of virus attachment proteins Single hybrid motif Rudiment single hybrid motif Duplicated hybrid motif AFP III-like Head decoration protein D (gpd, major capsid protein D) Urease, beta-subunit dutpase-like Tlp20, baculovirus telokin-like protein Hedgehog/intein (Hint) LexA/Signal peptidase Mss4-like Cyanovirin-N Head-binding of phage P22 tailspike protein E2 regulatory, transactivation Composite of metallo-dependent hydrolases Epsilon subunit of F1F0-ATP synthase N-terminal Triosephosphate isomerase (TIM) Ribulose-phoshate binding barrel Thiamin phosphate synthase FMN-linked oxidoreductases Inosine monophosphate dehydrogenase (IMPDH) PLP-binding barrel NAD(P)-linked oxidoreductase (Trans)glycosidases Metallo-dependent hydrolases Aldolase Enolase C-terminal -like Phosphoenolpyruvate/pyruvate Malate synthase G RuBisCo, C-terminal Xylose isomerase-like Bacterial luciferase-like Nicotinate/Quinolinate PRTase C-terminal -like PLC-like phosphodiesterases Cobalamin (vitamin B12)-dependent enzymes trna-guanine transglycosylase Dihydropteroate synthetase-like UROD/MetE-like FAD-linked oxidoreductase NAD(P)-binding Rossmann-fold s FAD/NAD(P)-binding Nucleotide-binding MurCD N-terminal Glycosyl hydrolases family 6, cellulases PFL-like glycyl radical enzymes Phosphohistidine LeuD/IlvD-like Carbamoyl phosphate synthetase, small subunit N-terminal PA GroEL apical -like Barstar-related Ribosomal protein L32e RNI-like L -like Outer arm dynein light chain Ribosomal proteins L15p and L18e CRAL/TRIO SpoIIaa-like ClpP/crotonase BRCT Lumazine synthase Caspase-like Uracil-DNA glycosylase-like FabD/lysophospholipase-like Initiation factor IF2/eIF5b, Ribosomal protein L Ribosomal protein L CheY-like Toll/Interleukin receptor TIR Hypothetical protein MTH Succinyl-CoA synthetase s Flavoproteins Cobalamin (vitamin B12)-binding N5-CAIR mutase (phosphoribosylaminoimidazole carboxylase, PurE) SGNH hydrolase Beta-D-glucan exohydrolase, C-terminal Formate/glycerate dehydrogenase catalytic -like Type II 3-dehydroquinate dehydratase N-(deoxy)ribosyltransferase-like Ribosomal protein S Class I glutamine amidotransferase-like Methylglyoxal synthase-like Ferredoxin reductase-like, C-terminal NADP-linked Nucleotidylyl transferase Adenine nucleotide alpha hydrolases-like UDP-glucose/GDP-mannose dehydrogenase C-terminal Nucleoside phosphorylase/phosphoribosyltransferase catalytic Cryptochrome/photolyase, N-terminal PreATP-grasp DHS-like NAD/FAD-binding Tubulin nucleotide-binding -like Isochorismatase-like hydrolases Homo-oligomeric flavin-containing Cys decarboxylases, HFCD Thiamin diphosphate-binding fold (THDP-binding) P-loop containing nucleoside triphosphate hydrolases PTS IIb component Nicotinate mononucleotide:5,6-dimethylbenzimidazole phosphoribosyltransferase (CobT) Methylesterase CheB, C-terminal Subtilisin-like Arginase/deacetylase CoA-dependent acyltransferases Phosphotyrosine protein phosphatases I PTS system IIB component-like (Phosphotyrosine protein) phosphatases II Rhodanese/Cell cycle control phosphatase Thioredoxin-like RNA 3'-terminal phosphate cyclase, RPTC, insert TK C-terminal -like PK C-terminal -like ATP synthase (F1-ATPase), gamma subunit Macro -like