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PMC:7081066 JSONTXT 24 Projects

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Id Subject Object Predicate Lexical cue
T1 0-92 Sentence denotes Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor:
T2 93-114 Sentence denotes An in silico analysis
T3 116-124 Sentence denotes Abstract
T4 125-189 Sentence denotes Many human viral diseases are a consequence of a zoonotic event.
T5 190-369 Sentence denotes Some of the diseases caused by these zoonotic events have affected millions of people around the world, some of which have resulted in high rates of morbidity/mortality in humans.
T6 370-488 Sentence denotes Changes in the viral proteins that function as ligands of the host receptor may promote the spillover between species.
T7 489-632 Sentence denotes The most recent of these zoonotic events that have caused an ongoing epidemic of high magnitude is the Covid-19 epidemics caused by SARS-CoV-2.
T8 633-794 Sentence denotes The aim of this study was to determine the mutation(s) in the sequence of the spike protein of the SARS-CoV-2 that might be favoring human to human transmission.
T9 795-916 Sentence denotes An in silico approach was performed, and changes were detected in the S1 subunit of the receptor-binding domain of spike.
T10 917-1098 Sentence denotes The observed changes have significant effect on SARS-CoV-2 spike/ACE2 interaction and produce a reduction in the binding energy, compared to the one of the Bat-CoV to this receptor.
T11 1099-1264 Sentence denotes The data presented in this study suggest a higher affinity of the SARS-Cov-2 spike protein to the human ACE2 receptor, compared to the one of Bat-CoV spike and ACE2.
T12 1265-1339 Sentence denotes This could be the cause of the rapid viral spread of SARS-CoV-2 in humans.
T13 1341-1353 Sentence denotes Introduction
T14 1354-1651 Sentence denotes Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV), and the recently identified novel Coronavirus (SARS-CoV-2) belong to the Coronaviridae family, genus Betacoronavirus, that has been related to important epidemiological outbreaks.
T15 1652-1736 Sentence denotes These are enveloped viruses with a positive-sense single-strand RNA of around 32 Kb.
T16 1737-1852 Sentence denotes The viral particles contain four main structural proteins: the spike, membrane, envelope protein, and nucleocapsid.
T17 1853-1995 Sentence denotes The spike protein protrudes from the envelope of the virion and plays a pivotal role in the receptor host selectivity and cellular attachment.
T18 1996-2166 Sentence denotes Strong scientific evidence showed that SARS and SARS-CoV-2 spike proteins interact with angiotensin-converting enzyme 2 (ACE2) (Chen et al 2020[2]; Wan et al., 2020[16]).
T19 2167-2304 Sentence denotes Also, other cellular receptors play a secondary role in the viral attachment, as the C-type lectin CD209L, and DC-SIGN binds to SARS-CoV.
T20 2305-2600 Sentence denotes However, ACE2 appears to be the key functional receptor for the SARS-CoV (Coutard et al., 2020[3]; Satija and Lal, 2007[12]) and probably for SARS-CoV-2 (Walls et al., 2020[15]) The interaction between the viral protein and its cell membrane receptor is a critical step in the replication cycle.
T21 2601-2686 Sentence denotes Furthermore, the efficiency of viral infection is strongly dependent on this process.
T22 2687-2768 Sentence denotes Several physicochemical factors are associated with protein-protein interactions.
T23 2769-2900 Sentence denotes These factors are determined by the nature of residues and the type of chemical interactions occurring between ligand and receptor.
T24 2901-3066 Sentence denotes Thus, the presence of residues that produce an energetically favored interaction (lower free energy) may drive binding kinetics and finally lead to the fusion event.
T25 3067-3222 Sentence denotes Based on that, this study aimed to evaluate the energetic profile of the interaction between the SARS-CoV-2 spike protein and the human cell receptor ACE2.
T26 3224-3245 Sentence denotes Materials and Methods
T27 3247-3264 Sentence denotes Sequence analysis
T28 3265-3402 Sentence denotes Sequences analyzed were individually retrieved from GenBank (accession numbers are shown in the phylogenetic tree, see Figure 1(Fig. 1)).
T29 3403-3610 Sentence denotes The sequence used for the modeling process and construct the spike protein model of SARS-CoV2 were obtained from the protein database and correspond to 6ACC (SARS spike protein) and 6ACD (Bat-spike protein).
T30 3612-3628 Sentence denotes Protein modeling
T31 3629-3870 Sentence denotes Homology structural models of viral spike protein from SARS-CoV-2 (QHO62112.1) and Bat-CoV (AAZ67052.1) were built by using the tools of the SWISS-MODEL modeling server and the DeepView/Swiss-PdbViewer 4.01 software (Arnold et al., 2006[1]).
T32 3871-3948 Sentence denotes Several models were obtained and the quality of each structure was evaluated.
T33 3949-4068 Sentence denotes The best model for SARS-CoV-2 spike was obtained using the crystal structure of SARS-CoV spike protein (PDB code 6ACC).
T34 4069-4183 Sentence denotes On the other hand, for Bat-CoV, the best model was obtained using as template the crystal structure PDB code 6ACD.
T35 4184-4254 Sentence denotes These models were subjected to further protein structure optimization.
T36 4255-4341 Sentence denotes Hydrogen atoms were added and the partial charges were assigned for energy refinement.
T37 4342-4394 Sentence denotes The protein model was embedded in a 100 Å water box.
T38 4395-4585 Sentence denotes Then, energy minimization was performed while applying constraints to the protein backbone to preserve global folding and optimizing the relative position of the water molecules and protein.
T39 4586-4683 Sentence denotes The obtained systems underwent MD simulations using NAMD as described by Ortega et al. (2019[8]).
T40 4684-4830 Sentence denotes All MD simulations described in this study were performed with NAMD 2.12 (Phillips et al., 2005[10]), Vega ZZ 3.1.0.21 (Pedretti et al., 2004[9]).
T41 4831-4916 Sentence denotes CHARMM force field (Vanommeslaeghe et al., 2010[14]) and Gasteiger charges were used.
T42 4917-4997 Sentence denotes The obtained structures represent the lowest energy frame of the MD simulations.
T43 4998-5135 Sentence denotes The quality of the models was established with ProSA (Wiederstein and Sippl, 2007[17]) and PROCHECK programs (Laskowski et al., 1993[4]).
T44 5137-5160 Sentence denotes Protein-protein docking
T45 5161-5282 Sentence denotes Crystal structure for SARS-CoV spike (PDB code 6ACK) and ACE2 (PDB code 1R42) were downloaded from the Protein Data Bank.
T46 5283-5341 Sentence denotes Also, the homology model for SARS-CoV-2 spike was assayed.
T47 5342-5397 Sentence denotes Protein preparation was carried out as described above.
T48 5398-5547 Sentence denotes Then, binding patterns and affinity estimations for the interaction between the viral spike and ACE2 receptor were performed using molecular docking.
T49 5548-5730 Sentence denotes This process was performed through two steps; first, a blind docking between ligand (spike protein) and receptor (ACE2) was performed using Z-dock software (Pierce et al., 2014[11]).
T50 5731-5854 Sentence denotes Then, the resulting docking data were processed and analyzed by using the tools of PRODIGY software (Xue et al., 2016[19]).
T51 5855-5975 Sentence denotes Finally, results were clustered and analyzed considering binding energies and main interacting residues in each complex.
T52 5977-5984 Sentence denotes Results
T53 5986-6059 Sentence denotes Homology analysis of the spike proteins of SARS-CoVs and related Bat-CoVs
T54 6060-6179 Sentence denotes Phylogenetic analysis of the spike protein sequences of SARS-CoV-2 and Bat-CoVs, SARS-CoV is shown in Figure 1(Fig. 1).
T55 6180-6467 Sentence denotes The results are in agreement with recent reports of an independent introduction of SARS-CoV-2 from a Bat-CoV, different from the spillover which led to the introduction of SARS-CoV, being the Bat-CoV of Rhinolophus affinis the probable ancestor of this new virus (Wong et al., 2020[18]).
T56 6468-6584 Sentence denotes Indeed, the sequences of the whole spike of this Bat-CoV and of SARS-CoV-2 share 97.7 % identity (Figure 1(Fig. 1)).
T57 6585-6719 Sentence denotes More divergence is found however in the S1 subunit, particularly in the Receptor Binding Domain (RBD) of the different spike proteins.
T58 6720-6925 Sentence denotes SARS-CoV and Bat-CoV from Rhinolophus sinicus (originally signaled as the most closely related virus to SARS-CoV-2) exhibit several amino acid substitutions and deletions in the RBD compared to SARS-CoV-2.
T59 6926-7093 Sentence denotes The RBD of Bat-CoV from Rhinolophus affinis, although more closely related to the one of SAS-CoV-2, also displayed several amino acid substitutions (Figure 2(Fig. 2)).
T60 7095-7138 Sentence denotes Structural analysis of Spike-ACE2 complexes
T61 7139-7380 Sentence denotes The crystal structures of the spike protein of SARS-CoV and homology models of Bat-CoV (accession number MG772933), Bat-CoV of Rhinolophus sinicus, and SARS-CoV-2 interacting with the putative binding domain site in human ACE2 were analyzed.
T62 7381-7453 Sentence denotes The interaction pattern between the three viral spikes is quite similar.
T63 7454-7681 Sentence denotes The main region of interaction with the putative cellular receptor counter-part is formed by fifteen residues ordered into a beta-sheet conformation surrounded by two capping loops (Figure 3(Fig. 3) and Supplementary Figure 1).
T64 7682-7903 Sentence denotes Interestingly, sequence comparison between SARS-CoV-2 and SARS-CoV revealed that the residues present in the receptor-interacting motive are highly conserved with 70 % identity, sharing nine residues between both viruses.
T65 7904-8049 Sentence denotes In the SARS-CoV RBD are present residues that allowed the interspecies infection, known as Y442, L472, N479, D480, and T487 (Lu et al., 2015[6]).
T66 8050-8202 Sentence denotes However, in SARS-CoV-2, slight modification of some residues could improve the interaction with the human cellular receptor: L455, F486, Q493, and N501.
T67 8203-8336 Sentence denotes In SARS-CoV, two main residues (479 and 487) have been associated to the recognition of the human ACE2 receptor (Lu et al., 2015[6]).
T68 8337-8432 Sentence denotes These residues suffered a punctual mutation from civet to human, K479N and S487T (Li, 2013[5]).
T69 8433-8523 Sentence denotes In the SARS-CoV-2, the residues corresponding to N479 correspond to Q493 and T487 to N501.
T70 8524-8636 Sentence denotes These changes in the SARS-CoV-2 represent energetically favorable changes for the interaction with the receptor.
T71 8637-8798 Sentence denotes The local environment present in the ACE2 receptor allows these mutations to produce a significant number of electrostatic stabilizing interactions (Table 1(Tab.
T72 8799-8803 Sentence denotes 1)).
T73 8804-8993 Sentence denotes Furthermore, as mentioned previously, the presence of the two capping loops in the binding domain is likely producing a stabilization effect over the interaction with the cellular receptor.
T74 8994-9108 Sentence denotes Our models showed that these capping loops appear in both human-infecting viruses but are absent in the bat virus.
T75 9109-9278 Sentence denotes The data showed here strongly suggest that these capping loops produce an increase in the electrostatic interactions between the spike protein and the cellular receptor.
T76 9279-9515 Sentence denotes In SARS-CoV, the residues present in these capping loops showing direct interaction with the receptor are R426, S432, T433, Y436, P462, D463, S472, and N473 and in SARS-CoV-2 are V445, Y449, Y473, Q474, A475, E484, G485, F486, and N487.
T77 9516-9588 Sentence denotes The counter-pairs located in the ACE2 receptor are shown in Table 1(Tab.
T78 9589-9592 Sentence denotes 1).
T79 9593-9664 Sentence denotes Altogether, the higher number of protein-protein contacts (Table 2(Tab.
T80 9665-9836 Sentence denotes 2)) and the longer capping loops could explain the increase in binding affinities in SARS-CoV-2 (-15.7 Kcal/mol) in comparison with SARS-CoV (-14.1 Kcal/mol) (Table 3(Tab.
T81 9837-9841 Sentence denotes 3)).
T82 9842-10023 Sentence denotes Thus, these loops could play an important role together with the punctual mutations being an interesting clue to determine the host receptor specificity for the viral spike protein.
T83 10025-10035 Sentence denotes Discussion
T84 10036-10153 Sentence denotes Several amino acid substitutions in RBD were identified in the SARS-CoV-2 RBD compared to Bat-SARS-CoVs and SARS-CoV.
T85 10154-10300 Sentence denotes Mutations in the spike protein could change the tropism of a virus, including new hosts or increasing viral pathogenesis (Shang et al., 2020[13]).
T86 10301-10396 Sentence denotes HIV infection is a good model of change in viral tropism by mutations in the envelope proteins.
T87 10397-10503 Sentence denotes These mutations switch co-receptor use (CCR5 to CXCR4) increasing the viral pathogenesis (Mosier 2009[7]).
T88 10504-10683 Sentence denotes Interestingly, our data showed that these changes are not only related to the ability of interaction with the human ACE2 receptor but also for improving this receptor recognition.
T89 10684-10894 Sentence denotes The presence of two loops around the RBD of SARS-CoV-2 might be promoting the interaction with the ACE2 receptor, improving the binding to this receptor by increasing the number of atoms involved (Tables 1(Tab.
T90 10895-10908 Sentence denotes 1) and 2(Tab.
T91 10909-10913 Sentence denotes 2)).
T92 10914-11069 Sentence denotes The amino acid substitutions and the longer capping loops could explain the increase in binding affinities in SARS-CoV-2 compared to SARS-CoV (Table 1(Tab.
T93 11070-11074 Sentence denotes 1)).
T94 11075-11188 Sentence denotes Higher affinity values might be related to the dynamic of infection and the rapid spread observed for this virus.
T95 11189-11248 Sentence denotes The origin of the SARS-CoV-2 has been not fully elucidated.
T96 11249-11509 Sentence denotes While this study was in course, another study of Wong et al. (2020[18]), showed a high similarity at protein level in the RBD among the coronaviruses isolated from the recent outbreak (SARS-CoV-2), those isolated from pangolin and Rhinolophus affinis (RaTG13).
T97 11510-11681 Sentence denotes The authors also suggest that Pangolin might be the intermediate host, with a 98 % identity with the human virus, at the receptor binding motif, between the bat and human.
T98 11682-11830 Sentence denotes The spike model of RaTG13 is quite similar to that obtained from SARS-CoV and SARS-CoV-2 and the loops in the RBD are also present (data not shown).
T99 11831-11911 Sentence denotes The protein sequence of the receptor binding motif, has 5 important amino acids.
T100 11912-12175 Sentence denotes When comparing the sequence of SARS-CoV-2 with that of the isolated viruses of pangolin and Rhinolophus affinis, 1 and 4 differences are observed respectively in the amino acids considered key for the union with ACE2 (Yan et al., 2020[20]; Wong et al., 2020[18]).
T101 12176-12327 Sentence denotes These differences should mean slightly less favorable binding energies between these viruses with ACE2 compared to the SARS-CoV-2, shown in this study.
T102 12328-12558 Sentence denotes Thus, the loops observed in the spike protein of SARS-CoV-2 could play an important role together with the amino acid substitutions, being an interesting clue to determine the host receptor specificity for the viral spike protein.
T103 12559-12716 Sentence denotes Altogether, structural changes and residues composition in the viral spike protein could be associated with increased infection kinetics and viral spreading.
T104 12717-12901 Sentence denotes Comparative studies to determine the impact in vitro of the mutation and loops in RBD of SARS-CoV and SARS-CoV-2 are required in order to predict possible zoonotic event in the future.
T105 12903-12925 Sentence denotes Supplementary Material
T106 12926-12951 Sentence denotes Supplementary information
T107 12953-13034 Sentence denotes Table 1 Residues involved in the Interaction between viral spike and ACE2 (SARS)
T108 13035-13112 Sentence denotes Table 2 Number of protein-protein contacts (PPC) between CoV spikes and ACE2
T109 13113-13249 Sentence denotes Table 3 Binding affinity (ΔG) and dissociation constant (Kd) predicted values for the interaction between viral spike and ACE2 receptor
T110 13250-13333 Sentence denotes Figure 1 Phylogenetic analysis of SARS-CoV-2 and other coronavirus spike proteins.
T111 13334-13415 Sentence denotes Phylogenetic tree constructed with Poisson correction and 100 bootstrap replicas.
T112 13416-13468 Sentence denotes The sequences are named with their accession number.
T113 13469-13543 Sentence denotes Percent homology with SARS-CoV-2 spike protein is shown for some proteins.
T114 13544-13664 Sentence denotes Figure 2 Receptor Binding Domain of the spike protein sequence alignment of SARS-CoV-2 and other related Coronaviruses.
T115 13665-13792 Sentence denotes Sequence aligment for the interacting domain of SARS-CoV-2 (MN938384), Bat-CoV (MN996532 and MG772933) and SARS-CoV (NC004718).
T116 13793-13993 Sentence denotes The key amino acids described for the interaction with ACE2 are shown in red, and in blue others amino acid related with the interaction in SARS-CoV2. (Lines (-) = same amino acid, dots (.) =deletion)
T117 13994-14031 Sentence denotes Figure 3 Coronavirus spike proteins.
T118 14032-14148 Sentence denotes The spike proteins in complex with the RBD of ACE2 (dark pink) are shown A) Bat-CoV, B) SARS-CoV, and C) SARS-CoV-2.
T119 14149-14250 Sentence denotes A comparison between the three spike proteins are shown in D and a 45 degree turn is also shown in E.
T120 14251-14375 Sentence denotes The location of the main residues mutated in SARS-CoV (position 479 and 487) and SARS-CoV-2 are shown in F (green and blue).