LitCovid-sentences  

PMC:7128678 / 6519-27384 JSONTXT 13 Projects

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Id Subject Object Predicate Lexical cue
T49 0-10 Sentence denotes 3 Results
T50 12-82 Sentence denotes 3.1 Structural and conformational analysis of CLQ and CLQ-OH in water
T51 83-151 Sentence denotes The chemical structures of CLQ and CLQ-OH are shown in Fig. 1 (a,b).
T52 152-253 Sentence denotes The only difference between the two molecules is the presence of a terminal hydroxyl group in CLQ-OH.
T53 254-359 Sentence denotes This OH group has a marked influence on the conformation and water-solubilization properties of the drug.
T54 360-466 Sentence denotes CLQ-OH may adopt a wide range of conformations, the most stable being the extended one shown in Fig. 1(c).
T55 467-686 Sentence denotes When immersed in a periodic box of 31.5 Å2 with 1042 water molecules, the system reached, at equilibrium, an estimated energy of interaction of -92 kJ.mol−1, accounting for 56 water molecules solvating CLQ-OH Fig. 1(d).
T56 687-801 Sentence denotes In contrast, due to an intramolecular hydrophobic effect, CLQ appeared to be more condensed than CLQ-OH Fig. 1(e).
T57 802-915 Sentence denotes At equilibrium, CLQ was surrounded by 58 water molecules with an energy of interaction of -79 kJ.mol−1 Fig. 1(f).
T58 916-1126 Sentence denotes Fig. 1 Chemical structure of chloroquine (CLQ) and hydroxychloroquine (CLQ-OH). (a) CLQ. (b) CLQ-OH. (c) CLQ-OH extended conformer. (d) CLQ-OH in water. (e) Typical condensed conformer of CLQ. (f) CLQ in water.
T59 1127-1257 Sentence denotes The molecules in (c–f) are shown in either tube or sphere rendering (carbon, green; nitrogen, blue; oxygen, red; hydrogen, white).
T60 1258-1335 Sentence denotes In (c) and (e), the chlorine atom of CLQ and CLQ-OH is indicated by an arrow.
T61 1336-1502 Sentence denotes These water-compatible conformations of CLQ and CLQ-OH were used as initial conditions for studying the interaction of these drugs with sialic acids and gangliosides.
T62 1504-1560 Sentence denotes 3.2 Sialic acids as molecular targets of CLQ and CLQ-OH
T63 1561-1645 Sentence denotes Neu5Ac is the predominant sialic acid found in human glycoproteins and gangliosides.
T64 1646-1813 Sentence denotes When CLQ was merged with Neu5Ac, a quasi-instantaneous fit occurred between the two molecules, whose global shapes in water are geometrically complementary Fig. 2 (a).
T65 1814-1938 Sentence denotes This is particularly obvious in the views of the CLQ–Neu5Ac complex in mixed surface/balls and sticks rendition Fig. 2(a,b).
T66 1939-2107 Sentence denotes The interaction was driven by the positioning of the negative charge of the carboxylate group of Neu5Ac and one of the two cationic charges of CLQ (pKa 10.2) Fig. 2(c).
T67 2108-2183 Sentence denotes The energy of interaction of this complex was estimated to be -47 kJ.mol−1.
T68 2184-2409 Sentence denotes As coronaviruses preferentially interact with 9-O-acetyl-N-acetylneuraminic acid (9-O-SIA) [10], this study used a similar molecular modelling approach to assess whether CLQ could also interact with this specific sialic acid.
T69 2410-2517 Sentence denotes A good fit between CLQ and 9-O-SIA was obtained Fig. 2(d–f), with an energy of interaction of -45 kJ.mol−1.
T70 2518-2667 Sentence denotes In this case, the carboxylate group of the sialic acid interacted with the cationic group of the nitrogen-containing ring of CLQ (pKa 8.1) Fig. 2(d).
T71 2668-2742 Sentence denotes The complex was further stabilized by OH-π and van der Waals interactions.
T72 2743-2891 Sentence denotes Fig. 2 Molecular modelling of chloroquine (CLQ) interaction with sialic acids. (a,b) Surface representation of the CLQ–sialic acid (Neu5Ac) complex.
T73 2892-2936 Sentence denotes Two opposite views of the complex are shown.
T74 2937-3269 Sentence denotes Note the geometric complementarity between the L-shape conformer of CLQ dissolved in water (in blue) and Neu5Ac (in red). (c) Neu5Ac bound to CLQ via a combination of CH-π and electrostatic interactions with one of the cationic groups of CLQ (+). (d) Molecular modelling of CLQ bound to N-acetyl-9-O-acetylneuraminic acid (9-O-SIA).
T75 3270-3470 Sentence denotes From right to left, the dashed lines indicate a series of van der Waals, OH-π and electrostatic contacts with both cationic groups of CLQ (+). (e,f) Surface representations of the CLQ–9-O-SIA complex.
T76 3471-3557 Sentence denotes Next, CLQ-OH was tested to assess whether it could, as CLQ, bind to 9-O-SIA (Fig. 3 ).
T77 3558-3749 Sentence denotes The complex obtained with CLQ-OH was very similar to that obtained with CLQ [compare Fig. 3(a,b) with Fig. 2(e,f), although several conformational adjustments occurred during the simulations.
T78 3750-3886 Sentence denotes Interestingly, the OH group of CLQ-OH reinforced the binding of CLQ to sialic acid through establishment of a hydrogen bond Fig. 3(c,d).
T79 3887-4145 Sentence denotes Overall, this hydrogen bond compensated for the slight loss of energy caused by the conformational rearrangement, and the energy of interaction of the complex was estimated to be -46 kJ.mol−1, which is very close to the value obtained for CLQ (-45 kJ.mol−1).
T80 4146-4328 Sentence denotes Fig. 3 Molecular modelling of hydroxychloroquine (CLQ-OH) interaction with sialic acids. (a,b) Surface representation of CLQ-OH bound to N-acetyl-9-O-acetylneuraminic acid (9-O-SIA).
T81 4329-4373 Sentence denotes Two opposite views of the complex are shown.
T82 4374-4575 Sentence denotes Note the geometric complementarity between CLQ-OH (in blue) and 9-O-SIA (in red). (c,d) Molecular mechanism of CLQ-OH binding to 9-O-SIA: combination of electrostatic interactions and hydrogen bonding.
T83 4577-4637 Sentence denotes 3.3 Molecular recognition of gangliosides by CLQ and CLQ-OH
T84 4638-4728 Sentence denotes In the respiratory tract, sialic acids are usually part of glycoproteins and gangliosides.
T85 4729-4874 Sentence denotes Molecular modelling approaches were used to assess whether CLQ and CLQ-OH can recognize sialic acid units in their natural molecular environment.
T86 4875-4990 Sentence denotes In these simulations, ganglioside GM1 was chosen as a representative example of human plasma membrane gangliosides.
T87 4991-5044 Sentence denotes A first series of simulations was performed with CLQ.
T88 5045-5164 Sentence denotes When merged with the ganglioside, CLQ had two distinct binding sites, both located in the polar saccharide part of GM1.
T89 5165-5260 Sentence denotes The first site was located at the tip of the saccharide moiety of the ganglioside Fig. 4 (a,b).
T90 5261-5320 Sentence denotes The energy of interaction was estimated to be -47 kJ.mol−1.
T91 5321-5455 Sentence denotes CLQ retained the typical L-shape structure of the water-soluble conformer bound to isolated sialic acids [compare Figs 2(c) and 4(a)].
T92 5456-5586 Sentence denotes From a mechanistic point of view, the carboxylate group of the sialic acid of GM1 was oriented towards the cationic groups of CLQ.
T93 5587-5727 Sentence denotes The rings of CLQ faced the N-acetylgalactosamine (GalNAc) residue of GM1, establishing both OH-π interaction and hydrogen bonding Fig. 4(b).
T94 5728-5843 Sentence denotes The second site was in a large area including both the ceramide–sugar junction and the saccharide moiety Fig. 4(c).
T95 5844-6033 Sentence denotes The chlorine atom of CLQ was oriented towards the ceramide axis, allowing the nitrogen-containing ring of CLQ to stack on to the pyrane ring of the first sugar residue [i.e. glucose (Glc)].
T96 6034-6188 Sentence denotes The perfect geometric complementarity of the two partners Fig. 4(c,d) accounted for a particularly high energy of interaction in this case (-61 kJ.mol−1).
T97 6189-6390 Sentence denotes Interestingly, there was no overlap between the two CLQ-binding sites on GM1, so the ganglioside could accommodate two CLQ molecules Fig. 4(e), reaching a global energy of interaction of -108 kJ.mol−1.
T98 6391-6491 Sentence denotes A similar situation was observed with CLQ-OH, which occupies the same binding site as CLQ Fig. 4(f).
T99 6492-6647 Sentence denotes In this case, the energy of interaction was further increased by stabilizing contacts established between the two CLQ-OH molecules, reaching -120 kJ.mol−1.
T100 6648-6770 Sentence denotes Overall, these data showed that CLQ and CLQ-OH have a good fit for sialic acids, either isolated or bound to gangliosides.
T101 6771-6890 Sentence denotes Fig. 4 Molecular modelling simulations of chloroquine (CLQ) and hydroxychloroquine (CLQ-OH) binding to ganglioside GM1.
T102 6891-7341 Sentence denotes The surface electrostatic potential of GM1 indicates a non-polar, membrane-embedded part corresponding to ceramide (white areas), and an acidic part protruding in the extracellular space corresponding to the sialic-acid-containing saccharide part (red areas). (a) CLQ bound to the tip of the carbohydrate moiety of GM1. (b) Molecular mechanism of CLQ–ganglioside interactions. (c) Molecular dynamics simulations revealed a second site of interaction.
T103 7342-7857 Sentence denotes In this case, the aromatic cycles of CLQ are positioned at the ceramide–sugar junction, whereas the nitrogen atoms interact with the acidic part of the ganglioside (not illustrated). (d,e) Surface views of GM1 complexed with one (d) or two (e) CLQ molecules (both in blue), illustrating the geometric complementarity of GM1 and CLQ molecules. (f) One GM1 molecule can also accommodate two distinct CLQ-OH molecules simultaneously, after slight rearrangement allowing increased fit due to CLQ-OH/CLQ-OH interactions.
T104 7858-7965 Sentence denotes To improve clarity, CLQ-OH molecules bound to GM1 are represented in two distinct colours (blue and green).
T105 7967-8026 Sentence denotes 3.4 Structural analysis of the NTD of SARS-CoV-2 S protein
T106 8027-8202 Sentence denotes The next step of this study was to determine how SARS-CoV-2 could interact with plasma membrane gangliosides, and whether such interaction could be affected by CLQ and CLQ-OH.
T107 8203-8282 Sentence denotes The global structure of the SARS-CoV-2 S protein [16] is shown in Fig. 5 (a–d).
T108 8283-8438 Sentence denotes It consists of a trimer of S proteins, each harbouring two distinct domains distant from the viral envelope: the receptor-binding region (RBD) and the NTD.
T109 8439-9131 Sentence denotes Fig. 5 Structural features of the SARS-CoV-2 spike (S) protein. (a) Trimeric structure (each S protein has a distinct surface colour, ‘blue’, ‘yellow’ and ‘purple’). (b) Ribbon representation of ‘blue’ S protein in the trimer (α-helix, red; β-strand, blue; coil, grey). (c) Surface structure of the ‘blue’ S protein isolated from the trimer. (d) Ribbon structure of the ‘blue’ S protein. (e) Zoom on the N-terminal domain (NTD) of the ‘blue’ S protein. (f,g) Molecular model of a minimal NTD obtained with Hyperchem [ribbon in representation in (f), surface rendering in (g)]. (h) Highlighting of the amino acid residues of the NTD that could belong to a potential ganglioside-binding domain.
T110 9132-9374 Sentence denotes It was reasoned that if the RBD is engaged in functional interactions with the ACE-2 receptor, it would be interesting to search for potential ganglioside-binding sites on the other cell-accessible domain of the S glycoprotein (i.e. the NTD).
T111 9375-9430 Sentence denotes The NTD contains approximately 290 amino acid residues.
T112 9431-9622 Sentence denotes The tip of the NTD was of particular interest, as it displays a flat interface Fig. 5(f) ideally positioned for targeting a ganglioside-rich plasma membrane microdomain, such as a lipid raft.
T113 9623-9787 Sentence denotes The amino acid sequence of the planar interfacial surface located at the tip of the NTD was analysed for the presence of consensus ganglioside-binding domains [20].
T114 9788-9895 Sentence denotes These motifs are constituted by a triad of mandatory amino acid residues such as (K,R)-Xn-(F,Y,W)-Xn-(K,R).
T115 9896-10025 Sentence denotes The Xn intercalating segments, usually four to five residues, may contain any amino acid, but often Gly, Pro and/or Ser residues.
T116 10026-10165 Sentence denotes The strict application of this algorithm did not allow the detection of any potential ganglioside-binding domain in this region of the NTD.
T117 10166-10273 Sentence denotes However, an intriguing over-representation of aromatic and basic residues was found in the 129–158 segment:
T118 10274-10313 Sentence denotes 129-KVCEFQFCNDPFLGVYYHKNNKSWMESEFR-158.
T119 10314-10435 Sentence denotes This 30-amino acid stretch also contains Gly, Pro and/or Ser residues that are often found in ganglioside-binding motifs.
T120 10436-10555 Sentence denotes These observations supported the notion that the tip of the NTD could display a large ganglioside-attachment interface.
T121 10557-10641 Sentence denotes 3.5 Molecular interactions between gangliosides and the NTD of SARS-CoV-2 S protein
T122 10642-10817 Sentence denotes Molecular dynamic simulations of a structural motif encompassing amino acid residues 100–175 of the NTD Fig. 5(f–h) merged with ganglioside GM1 further supported this concept.
T123 10818-10962 Sentence denotes As shown in Fig. 6 , the large flat area of this structural domain fitted very well with the protruding oligosaccharide part of the ganglioside.
T124 10963-11086 Sentence denotes Several amino acid residues appear to be critical for this interaction, especially Phe-135, Asn-137 and Arg-158 (Table 1 ).
T125 11087-11191 Sentence denotes Overall, the complex involved 10 amino acid residues for a total energy of interaction of -100 kJ.mol−1.
T126 11192-11371 Sentence denotes At this stage, it was observed that approximately 50% of the interface was involved in the complex, leaving the remaining 50% available for interaction with a second GM1 molecule.
T127 11372-11644 Sentence denotes As expected, merging a second GM1 molecule with the preformed GM1–NTD complex led to a trimolecular complex consisting of two gangliosides in a typical symmetrical chalice-like structure into which the NTD could insert its interfacial ganglioside-binding domain (Fig. 7 ).
T128 11645-11824 Sentence denotes The formation of this trimolecular complex was progressive, starting with a conformational rearrangement of the first ganglioside–NTD complex triggered by the second GM1 molecule.
T129 11825-11950 Sentence denotes The energy of interaction of the new complex was consistently increased by 37%, reaching an estimated value of -137 kJ.mol−1.
T130 11951-12115 Sentence denotes At this stage, attachment of the NTD to the ganglioside-rich microdomain involved the whole interface (i.e. 15 surface-accessible residues from Asp-111 to Ser-162).
T131 12116-12200 Sentence denotes The critical residues were Asp-111, Gln-134, Phe-135, Arg-158 and Ser-161 (Table 1).
T132 12201-12319 Sentence denotes Fig. 6 Molecular complex between the N-terminal domain (NTD) of SARS-CoV-2 spike protein and a single GM1 ganglioside.
T133 12320-12416 Sentence denotes The NTD is represented in ribbons superposed with a transparent surface rendering (light green).
T134 12417-12468 Sentence denotes Two symmetric views of the complex are shown (a,b).
T135 12469-12597 Sentence denotes The amino acid residues Q-134 to D-138 located in the centre of the ganglioside-binding domain are represented as green spheres.
T136 12598-12684 Sentence denotes The saccharide part of the ganglioside forms a landing surface for the tip of the NTD.
T137 12685-12800 Sentence denotes Table 1 Energy of interaction of each amino acid residue of SARS‐CoV‐2 spike protein in contact with GM1 molecules.
T138 12801-12853 Sentence denotes Amino acid residues Energy of interaction (kJ.mol‐1)
T139 12854-12882 Sentence denotes First step: one GM1 molecule
T140 12883-12896 Sentence denotes  Asp‐111 −5.6
T141 12897-12910 Sentence denotes  Lys‐113 −8.2
T142 12911-12924 Sentence denotes  Gln‐134 −8.6
T143 12925-12939 Sentence denotes  Phe‐135 −20.1
T144 12940-12953 Sentence denotes  Cys‐136 −7.0
T145 12954-12968 Sentence denotes  Asn‐137 −15.2
T146 12969-12982 Sentence denotes  Asp‐138 −6.4
T147 12983-12997 Sentence denotes  Arg‐158 −17.4
T148 12998-13011 Sentence denotes  Ser‐161 −9.7
T149 13012-13025 Sentence denotes  Ser‐162 −2.0
T150 13026-13039 Sentence denotes  Total −100.2
T151 13040-13070 Sentence denotes Second step: two GM1 molecules
T152 13071-13085 Sentence denotes  Asp‐111 −15.8
T153 13086-13100 Sentence denotes  Ser‐112 −10.7
T154 13101-13114 Sentence denotes  Lys‐113 −9.2
T155 13115-13129 Sentence denotes  Gln‐134 −11.2
T156 13130-13144 Sentence denotes  Phe‐135 −10.5
T157 13145-13158 Sentence denotes  Cys‐136 −6.2
T158 13159-13172 Sentence denotes  Asn‐137 −4.7
T159 13173-13186 Sentence denotes  Phe‐140 −5.2
T160 13187-13200 Sentence denotes  Gly‐142 −5.6
T161 13201-13214 Sentence denotes  Glu‐156 −9.0
T162 13215-13229 Sentence denotes  Phe‐157 −13.8
T163 13230-13244 Sentence denotes  Arg‐158 −19.8
T164 13245-13258 Sentence denotes  Tyr‐160 −3.2
T165 13259-13272 Sentence denotes  Ser‐161 −9.7
T166 13273-13286 Sentence denotes  Ser‐162 −2.0
T167 13287-13300 Sentence denotes  Total −136.6
T168 13301-13409 Sentence denotes Fig. 7 Molecular complex between the N-terminal domain (NTD) of SARS-CoV-2 spike protein and a dimer of GM1.
T169 13410-13467 Sentence denotes In (a), (c) and (d), the NTD is represented as in Fig. 4.
T170 13468-13533 Sentence denotes In (b), the surface of the NTD is shown without any transparency.
T171 13534-13656 Sentence denotes The amino acid residues Q-134 to S-162 belonging to the ganglioside-binding domain (GBD) are represented as green spheres.
T172 13657-13766 Sentence denotes Compared with a single GM1 molecule, the dimer of gangliosides forms a larger attractive surface for the NTD.
T173 13767-13862 Sentence denotes In the above view of (d), the anchorage of the NTD to the gangliosides is particularly obvious.
T174 13863-14081 Sentence denotes As chloroquine also interacts with the saccharide part of GM1, its presence would clearly mask most of the landing surface available for the NTD, preventing attachment of the virus to the plasma membrane of host cells.
T175 14083-14221 Sentence denotes 3.6 Potential coordinated interactions between SARS-CoV-2 and the plasma membrane of a host cell: key role of gangliosides in lipid rafts
T176 14222-14507 Sentence denotes Taken together, these data strongly support the concept of a dual receptor/attachment model for SARS-CoV-2, with the RBD domain being involved in ACE-2 receptor recognition, and the NTD interface responsible for finding a ganglioside-rich landing area (lipid raft) at the cell surface.
T177 14508-14617 Sentence denotes Such a dual receptor model, consistent with the topology of the SARS-CoV-2 S protein, is proposed in Fig. 8 .
T178 14618-14810 Sentence denotes With this model in mind, the potential effects of CLQ and CLQ-OH were studied, both of which, according to the molecular modelling data, have a high affinity for sialic acids and gangliosides.
T179 14811-14927 Sentence denotes Fig. 8 Dual recognition of gangliosides and angiotensin-converting enzyme-2 (ACE-2) by SARS-CoV-2 spike (S) protein.
T180 14928-15044 Sentence denotes The viral protein displays two distinct domains, the tips of which are available for distinct types of interactions.
T181 15045-15194 Sentence denotes The receptor-binding domain binds to the ACE-2 receptor, and the N-terminal domain (NTD) binds to the ganglioside-rich domain of the plasma membrane.
T182 15195-15428 Sentence denotes Lipid rafts, which are membrane domains enriched in gangliosides (in yellow) and cholesterol (in blue), provide a perfect attractive interface for adequately positioning the viral S protein at the first step of the infection process.
T183 15429-15685 Sentence denotes These structural and molecular modelling studies suggest that amino acid residues 111–162 of the NTD form a functional ganglioside-binding domain, the interaction of which with lipid rafts can be efficiently prevented by chloroquine and hydroxychloroquine.
T184 15687-15815 Sentence denotes 3.7 Molecular mechanism of CLQ and CLQ-OH antiviral effect: preventing SARS-CoV-2 S protein access to cell surface gangliosides
T185 15816-16021 Sentence denotes With the aim of establishing whether CLQ and CLQ-OH could prevent the attachment of SARS-CoV-2 to plasma membrane gangliosides, the initial NTD–GM1 complex was superposed with a drug–GM1 complex (Fig. 9 ).
T186 16022-16085 Sentence denotes To improve clarity, the ganglioside is not presented in Fig. 9.
T187 16086-16275 Sentence denotes This superposition shows that the NTD and the drug (CLQ-OH in this case) share the same spatial position when bound to GM1, so GM1 cannot bind the viral protein and the drug simultaneously.
T188 16276-16500 Sentence denotes This is due to the fact that the NTD and the drugs (CLQ and CLQ-OH) bind to GM1 with a similar mechanism controlled by a dyad of functional interactions: a hydrogen bond and a geometrically perfect CH-π stacking interaction.
T189 16501-16637 Sentence denotes In the case of the NTD, the hydrogen bond involves Asn-167, whereas CH-π stacking is mediated by the aromatic ring of Phe-135 Fig. 6(b).
T190 16638-16730 Sentence denotes On one hand, Asn-167 establishes a network of hydrogen bonds with the GalNAc residue of GM1.
T191 16731-16833 Sentence denotes On the other hand, the flat aromatic ring of Phe-135 stacks on to the cycle of the Glc residue of GM1.
T192 16834-16953 Sentence denotes In the case of CLQ and CLQ-OH, it is the nitrogen-containing ring of the drug that stacks on to the Glc ring Fig. 4(c).
T193 16954-17060 Sentence denotes Note that both the Phe-135 (in red) and CLQ-OH (in green) rings are located in the same position (Fig. 9).
T194 17061-17195 Sentence denotes The other CLQ-OH molecule, which covers the tip of the sugar part of the ganglioside, interacts with the GalNAc ganglioside Fig. 4(b).
T195 17196-17305 Sentence denotes When the NTD is bound to the ganglioside, the side chain of Asn-137 is found in this exact position (Fig. 9).
T196 17306-17474 Sentence denotes Thus, once two CLQ-OH (or two CLQ) molecules are bound to a ganglioside Fig. 4(e,f), any binding of a SARS-Cov-2 S protein to the same ganglioside is totally prevented.
T197 17475-17611 Sentence denotes The energy required to overcome this steric incompatibility is estimated to be several hundred kJ.mol−1, which is far too high to occur.
T198 17612-17670 Sentence denotes Fig. 9 Mechanism of action of hydroxychloroquine (CLQ-OH).
T199 17671-17777 Sentence denotes The N-terminal domain (NTD) bound to GM1 was superposed onto GM1 in interaction with two CLQ-OH molecules.
T200 17778-18050 Sentence denotes The models only show the NTD and both CLQ-OH molecules (not GM1, to improve clarity). (a,b) The aromatic ring of F-135 (in red), which stacks onto the glucose cycle of GM1, overlaps the aromatic CLQ-OH rings (in green) which also bind to GM1 via a CH-π stacking mechanism.
T201 18051-18486 Sentence denotes The N-137 residue of the NTD interacts with the N-acetylgalactosamine residue of GM1, but this interaction cannot occur in the presence of CLQ-OH as this part of GM1 is totally masked by the drug. (c,d) Superposition of the NTD surface (in purple) with the two CLQ-OH molecules bound to GM1, illustrating the steric impossibility that prevents NTD binding to GM1 when both CLQ-OH molecules are already interacting with the ganglioside.
T202 18488-18635 Sentence denotes 3.8 Sequence alignment analysis of SARS-CoV-2 and related coronavirus: evolution of the ganglioside-binding domain at critical amino acid residues
T203 18636-18846 Sentence denotes As CLQ and CLQ-OH are potential therapies for SARS-CoV-2 infection, it is important to check whether the amino acid residues identified as critical for ganglioside binding are conserved among clinical isolates.
T204 18847-18999 Sentence denotes The alignment of the 111–162 domain of 11 clinical isolates of SARS-CoV-2 from various geographic origins (including Asia and USA) is shown in Fig. 10 .
T205 19000-19132 Sentence denotes In this region, which contains the ganglioside-binding domain identified in the present report, all amino acids are fully conserved.
T206 19133-19340 Sentence denotes Interestingly, the motif is built like a giant consensus ganglioside-binding domain: a central region displaying the critical aromatic residue (Phe-135) and a basic residue at each end (Lys-113 and Arg-158).
T207 19341-19456 Sentence denotes In the middle of each stretch separating this typical triad, there is a N-glycosylation site (Asn-122 and Asn-149).
T208 19457-19662 Sentence denotes These last regions are not directly involved in ganglioside binding, so the oligosaccharide linked to these asparagine residues could be perfectly intercalated between the sugar head group of gangliosides.
T209 19663-19871 Sentence denotes Fig. 10 Amino acid sequence alignments of the ganglioside-binding domain (GBD) of the SARS-CoV-2 spike protein. (a) Clinical SARS-CoV-2 isolates aligned with the reference sequence (6VSB_A, fragment 111–162).
T210 19872-19941 Sentence denotes The amino acid residues involved in GM1 binding are indicated in red.
T211 19942-20118 Sentence denotes Two asparagine residues acting as glycosylation sites are highlighted in yellow. (b) Alignments of human and animal viruses compared with SARS-CoV-2 (6VSB_A, fragment 111–162).
T212 20119-20377 Sentence denotes Deletions are highlighted in green, amino acid changes in residues involved in ganglioside binding are highlighted in blue, conserved residues of the GBD are highlighted in red, and asparagine residues acting as glycosylation sites are highlighted in yellow.
T213 20378-20613 Sentence denotes It was also noted that the ganglioside-binding domain of the NTD is fully conserved in bat RaTG13, which indicates a close relationship between the bat coronavirus and the human isolates that are currently circulating around the world.
T214 20614-20865 Sentence denotes However, the motif is slightly different in other bat- and human-related coronaviruses (Fig. 10), suggesting a recent evolution which could explain, at least in part, why SARS-CoV-2 is more contagious than previously characterized human coronaviruses.