●I-TASSER ●QUARK ●LOMETS ●COACH ●COFACTOR ●MetaGO ●MUSTER ●CEthreader ●SEGMER ●FG-MD ●ModRefiner ●REMO ●DEMO ●SPRING ●COTH ●BSpred ●ANGLOR ●EDock ●BSP-SLIM ●SAXSTER ●FUpred ●ThreaDom ●ThreaDomEx ●EvoDesign ●GPCR-I-TASSER ●MAGELLAN ●BindProf ●BindProfX ●SSIPe ●ResQ ●IonCom ●STRUM ●DAMpred

●TM-score ●TM-align ●MM-align ●RNA-align ●NW-align ●LS-align ●EDTSurf ●MVP ●MVP-Fit ●SPICKER ●HAAD ●PSSpred ●3DRobot ●MR-REX ●I-TASSER-MR ●SVMSEQ ●NeBcon ●ResPRE ●WDL-RF ●ATPbind ●DockRMSD ●DeepMSA ●FASPR ●EM-Refiner

●BioLiP ●E. coli ●GLASS ●GPCR-HGmod ●GPCR-RD ●GPCR-EXP ●Tara-3D ●TM-fold ●DECOYS ●POTENTIAL ●RW/RWplus ●EvoEF ●HPSF ●THE-DB ●ADDRESS ●Alpaca-Antibody ●CASP7 ●CASP8 ●CASP9 ●CASP10 ●CASP11 ●CASP12 ●CASP13 ●CASP14

Table I: Monomer structures constructed by DEMO-EM.

NO.	Protein sequence translated from SARS-CoV-2 genome	DEMO-EM structure model and accuracy	Protein name and function (based on UniProt curation of SARS-CoV-2 proteome)	Solved experimental structure
1	>QHD43415_7 (L=83) SKMSDVKCTSVVLLSVLQQLRVESSSKLWAQCVQLHNDIL LAKDTTEAFEKMVSLLSVLLSMQGAVDINKLCEEMLDNRA TLQ	[Download] TM-score=0.97 MolProbity score=0.50	Non-structural protein 7 (nsp7). Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.	6M71(range:1-83);
2	>QHD43415_8 (L=198) AIASEFSSLPSYAAFATAQEAYEQAVANGDSEVVLKKLKK SLNVAKSEFDRDAAMQRKLEKMADQAMTQMYKQARSEDKR AKVTSAMQTMLFTMLRKLDNDALNNIINNARDGCVPLNII PLTTAAKLMVVIPDYNTYKNTCDGTTFTYASALWEIQQVV DADSKIVQLSEISMDNSPNLAWPLIVTALRANSAVKLQ	[Download] TM-score=0.94 MolProbity score=0.84	Non-structural protein 8 (nsp8). Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.	7CYQ(range:1-198);
3	>QHD43415_11 (L=932) SADAQSFLNRVCGVSAARLTPCGTGTSTDVVYRAFDIYND KVAGFAKFLKTNCCRFQEKDEDDNLIDSYFVVKRHTFSNY QHEETIYNLLKDCPAVAKHDFFKFRIDGDMVPHISRQRLT KYTMADLVYALRHFDEGNCDTLKEILVTYNCCDDDYFNKK DWYDFVENPDILRVYANLGERVRQALLKTVQFCDAMRNAG IVGVLTLDNQDLNGNWYDFGDFIQTTPGSGVPVVDSYYSL LMPILTLTRALTAESHVDTDLTKPYIKWDLLKYDFTEERL KLFDRYFKYWDQTYHPNCVNCLDDRCILHCANFNVLFSTV FPPTSFGPLVRKIFVDGVPFVVSTGYHFRELGVVHNQDVN LHSSRLSFKELLVYAADPAMHAASGNLLLDKRTTCFSVAA LTNNVAFQTVKPGNFNKDFYDFAVSKGFFKEGSSVELKHF FFAQDGNAAISDYDYYRYNLPTMCDIRQLLFVVEVVDKYF DCYDGGCINANQVIVNNLDKSAGFPFNKWGKARLYYDSMS YEDQDALFAYTKRNVIPTITQMNLKYAISAKNRARTVAGV SICSTMTNRQFHQKLLKSIAATRGATVVIGTSKFYGGWHN MLKTVYSDVENPHLMGWDYPKCDRAMPNMLRIMASLVLAR KHTTCCSLSHRFYRLANECAQVLSEMVMCGGSLYVKPGGT SSGDATTAYANSVFNICQAVTANVNALLSTDGNKIADKYV RNLQHRLYECLYRNRDVDTDFVNEFYAYLRKHFSMMILSD DAVVCFNSTYASQGLVASIKNFKSVLYYQNNVFMSEAKCW TETDLTKGPHEFCSQHTMLVKQGDDYVYLPYPDPSRILGA GCFVDDIVKTDGTLMIERFVSLAIDAYPLTKHPNQEYADV FHLYLQYIRKLHDELTGHMLDMYSVMLTNDNTSRYWEPEF YEAMYTPHTVLQ	[Download] TM-score=0.96 MolProbity score=0.81	RNA-directed RNA polymerase (RdRp). Responsible for replication and transcription of the viral RNA genome.	6M71(range:1-932);
4	>QHD43415_12 (L=601) AVGACVLCNSQTSLRCGACIRRPFLCCKCCYDHVISTSHK LVLSVNPYVCNAPGCDVTDVTQLYLGGMSYYCKSHKPPIS FPLCANGQVFGLYKNTCVGSDNVTDFNAIATCDWTNAGDY ILANTCTERLKLFAAETLKATEETFKLSYGIATVREVLSD RELHLSWEVGKPRPPLNRNYVFTGYRVTKNSKVQIGEYTF EKGDYGDAVVYRGTTTYKLNVGDYFVLTSHTVMPLSAPTL VPQEHYVRITGLYPTLNISDEFSSNVANYQKVGMQKYSTL QGPPGTGKSHFAIGLALYYPSARIVYTACSHAAVDALCEK ALKYLPIDKCSRIIPARARVECFDKFKVNSTLEQYVFCTV NALPETTADIVVFDEISMATNYDLSVVNARLRAKHYVYIG DPAQLPAPRTLLTKGTLEPEYFNSVCRLMKTIGPDMFLGT CRRCPAEIVDTVSALVYDNKLKAHKDKSAQCFKMFYKGVI THDVSSAINRPQIGVVREFLTRNPAWRKAVFISPYNSQNA VASKILGLPTQTVDSSQGSEYDYVIFTQTTETAHSCNVNR FNVAITRAKVGILCIMSDRDLYDKLQFTSLEIPRRNVATL Q	[Download] TM-score=0.98 MolProbity score=1.55	Helicase (Hel). Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.	5RL9(range:1-601);
5	>QHD43416 (L=1273) MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPD KVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFD NPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIV NNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVY SSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGY FKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQT LLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYN ENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRV QPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISN CVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSF VIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNN LDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPC NGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHA PATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFL PFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITP GTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGS NVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNS PRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI SVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFC TQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGF NFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDC LGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAG TITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQ KLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALN TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGR LQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRV DFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPA ICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNT FVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHT SPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDL QELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSC CSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT	[Download] TM-score=0.98 MolProbity score=0.93	Spike glycoprotein (S). Spike protein S1 (residue 13-685): attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes. Spike protein S2 (residue 686-1273): mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Spike protein S2' (residue 816-1273): acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.	6VYB (open state)(range:1-1273); 6VXX (closed state)(range:1-1273); 6LXT(range:912-988,1164-1202);
6	>QHD43417 (L=275) MDLFMRIFTIGTVTLKQGEIKDATPSDFVRATATIPIQAS LPFGWLIVGVALLAVFQSASKIITLKKRWQLALSKGVHFV CNLLLLFVTVYSHLLLVAAGLEAPFLYLYALVYFLQSINF VRIIMRLWLCWKCRSKNPLLYDANYFLCWHTNCYDYCIPY NSVTSSIVITSGDGTTSPISEHDYQIGGYTEKWESGVKDC VVLHSYFTSDYYQLYSTQLSTDTGVEHVTFFIYNKIVDEP EEHVQIHTIDGSSGVVNPVMEPIYDEPTTTTSVPL	[Download] TM-score=0.99 MolProbity score=0.91	ORF3a. Forms homotetrameric potassium sensitive ion channels (viroporin) and may modulate virus release. Up-regulates expression of fibrinogen subunits FGA, FGB and FGG in host lung epithelial cells. Induces apoptosis in cell culture. Downregulates the type 1 interferon receptor by inducing serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and increasing IFNAR1 ubiquitination	6XDC(range:1-275);

Table II: Complex structures constructed by DEMO-EM

NO.	DEMO-EM structure model	Protein name
1	[Download]	Chain A, B: ORF3a complex.
2	[Download]	Chain A, B, C, D, E, F: replication-transcription complex.
3	[Download]	Chain A, B, C: Spike protein complex.
4	[Download]	Chain A, B, C, E: RNA-dependent RNA polymerase.

• Xiaogen Zhou, Yang Li, Chengxin Zhang, Wei Zheng, Guijun Zhang, Yang Zhang. Progressive assembly of multi-domain protein structures from cryo-EM density maps. Nature Computational Science, in press, 2022.