LitCovid-sentences  

PMC:7605337 / 1941-11731 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T13 0-12 Sentence denotes Introduction
T14 13-148 Sentence denotes The novel coronavirus (nCOV-2019) outbreak emerging from China has become a global pandemic and a major threat for human public health.
T15 149-501 Sentence denotes According to the World Health Organization as of August 28th 2020, there has been about 25 million confirmed cases and approaching 900,000 deaths because of coronavirus in the world.1,2 Much of the human population including the United States of America were under lockdown or official stay-at-home orders to minimize the continued spread of the virus.
T16 502-570 Sentence denotes Coronaviruses are a family of single-stranded enveloped RNA viruses.
T17 571-1122 Sentence denotes Phylogenetic analysis of coronavirus genome has shown that nCOV-2019 belongs to the beta-coronavirus family, which also includes Middle East respiratory syndrome coronavirus (MERS-COV), severe acute respiratory syndrome coronavirus (SARS-COV), and bat-SARS-related coronaviruses.3,4 It is worth mentioning that SARS-COV, which was widespread in 2002 caused more than 8000 cases and about 800 deaths and MERS-COV in 2012 also spread in more than 25 countries, causing about 2500 cases and more than 850 deaths. (www.who.int/health-topics/coronavirus).5
T18 1123-1407 Sentence denotes In all coronaviruses, a homotrimeric spike glycoprotein on the virion’s envelope mediates coronavirus entry into host cells through a mechanism of receptor binding followed by fusion of viral and host membranes.3,6 Coronavirus spike protein contains two functional subunits S1 and S2.
T19 1408-1869 Sentence denotes The S1 subunit is responsible for binding to host cell receptor, and the S2 subunit is responsible for fusion of viral and host cell membranes.3,7 The spike protein in nCOV-2019 exists in a meta-stable pre-fusion conformation that undergoes a substantial conformational rearrangement to fuse the viral membrane with the host cell membrane.7,8 nCOV-2019 is closely related to bat coronavirus RaTG13 with about 93.1% sequence similarity in the spike protein gene.
T20 1870-2091 Sentence denotes The sequence similarity of nCOV-2019 and SARS-COV is less than 80% in the spike sequence.2 The S1 subunit in the spike protein includes a receptor binding domain (RBD) that recognizes and binds to the host cells receptor.
T21 2092-2795 Sentence denotes The RBD of nCOV-2019 shares 72.8% sequence identity to SARS-COV RBD and the root mean squared deviation (RMSD) for the structure between the two proteins is 1.2Å, which shows the high structural similarity.4,8,9 Experimental binding affinity measurements using surface plasmon resonance (SPR) have shown that nCOV-2019 spike protein binds its receptor human angiotensin converter enzyme (ACE2) with 10 to 20 fold higher affinity than SARS-COV binding to ACE2.7 Based on the sequence similarity between RBD of nCOV-2019 and SARS-COV and also the tight binding between the RBD of nCOV-2019 and ACE2, it is most probable that nCOV-2019 uses this receptor on human cells to gain entry into the body.3,6,7,10
T22 2796-2908 Sentence denotes The spike protein and specifically the RBD in coronaviruses have been a major target for therapeutic antibodies.
T23 2909-3142 Sentence denotes However, no monoclonal antibodies targeted to RBD have been able to bind efficiently and neutralize nCOV-2019.7,11 The core of nCOV-2019 RBD is a five-stranded antiparallel β-sheet with connected short α-helices and loops (Figure 1).
T24 3143-3242 Sentence denotes The binding interface of nCOV-2019 and SARS-COV with ACE2 is very similar with less than 1.3Å RMSD.
T25 3243-3401 Sentence denotes An extended insertion inside the core containing short strands, α-helices, and loops called the receptor binding motif (RBM) makes all the contacts with ACE2.
T26 3402-3531 Sentence denotes In nCOV-2019 RBD, the RBM forms a concave surface with a ridge loop on one side and it binds to a convex exposed surface of ACE2.
T27 3532-3601 Sentence denotes The overlay of SARS and nCOV-2019 RBD proteins is shown in Figure 1A.
T28 3602-3712 Sentence denotes The binding interface in nCOV-2019 contains loops L1 to L4 and short β-strands β5 and β6 and a short helix α5.
T29 3713-3821 Sentence denotes The location of RBM in nCOV-2019 RBD as well as different helices, strands, and loops is shown in Figure 1B.
T30 3822-3999 Sentence denotes Figure 1 (A) Superposition of the RBD of SARS-COV (yellow) and nCOV-2019 (red). (B) Different regions in the binding domain of nCOV-2019 defining the extended loop (nonyellow).
T31 4000-4132 Sentence denotes The sequence alignment between SARS-COV in human, SARS civet, Bat RaTG13 coronavirus, and nCOV-2019 in the RBM is shown in Figure 2.
T32 4133-4210 Sentence denotes There is a 50% sequence similarity between the RBM of nCOV-2019 and SARS-COV.
T33 4211-4382 Sentence denotes RBM mutations played an important role in the SARS epidemic in 2002.3,12 Two mutations in the RBM of SARS-2002 from SARS-Civet were observed from strains of these viruses.
T34 4383-4424 Sentence denotes These two mutations were K479N and S487T.
T35 4425-4529 Sentence denotes These two residues are close to the virus binding hotspots in ACE2 including hotspot-31 and hotspot-353.
T36 4530-4658 Sentence denotes Hotspot-31 centers on the salt-bridge between K31-E35 and hotspot-353 are centered on the salt-bridge between K353-E358 on ACE2.
T37 4659-5346 Sentence denotes Residues K479 and S487 in SARS-Civet are in close proximity with these hotspots and mutations at these residues caused SARS to bind ACE2 with significantly higher affinity than SARS-civet and played a major role in civet-to-human and human-to-human transmission of SARS coronavirus in 2002.3,13−15 Numerous mutations in the interface of SARS-COV RBD and ACE2 from different strains of SARS isolated from humans in 2002 have been identified and the effect of these mutations on binding ACE2 has been investigated by SPR.14,16 Two identified RBD mutations (Y442F and L472F) increased the binding affinity of SARS-COV to ACE2 and two mutations (N479K, T487S) decreased the binding affinity.
T38 5347-6298 Sentence denotes It was demonstrated that these mutations were viral adaptations to either human or civet ACE2.14,16 A pseudotyped viral infection assay of the interaction between different spike proteins and ACE2 confirmed the correlation between high affinity mutants and their high infection.16 Further investigation of RBD residues in binding of SARS-COV and ACE2 was performed through ala-scanning mutagenesis, which resulted in identification of residues that reduce binding affinity to ACE2 upon mutation to alanine.17 RBD mutations have also been identified in MERS-COV, which affected their affinity to receptor (DPP4) on human cells.14 Multiple monoclonal antibodies have been developed for SARS since 2002 that neutralized the spike glycoprotein on the SARS-COV surface.18−22 However, multiple escape mutations exist in the RBD of SARS-COV that affect neutralization with antibodies, which led to the use of a cocktail of antibodies as a robust treatment.23
T39 6299-6392 Sentence denotes Figure 2 Sequence comparison of the RBM in SARS-2002, SARS-civet, Bat RaTG13, and nCOV-2019.
T40 6393-6452 Sentence denotes Mutations from SARS-2002 to nCOV-2019 are marked with blue.
T41 6453-6503 Sentence denotes Important mutations in RBM are marked with yellow.
T42 6504-6609 Sentence denotes Red color shows the three-residue motif in SARS and civet and four-residue motif in RaTG13 and nCOV-2019.
T43 6610-6768 Sentence denotes Full genome analysis of nCOV-2019 in different countries and the receptor binding surveillance have shown multiple mutations in the RBD of glycosylated spike.
T44 6769-6893 Sentence denotes The GISAID database24 (www.gisaid.org/) contains genomes on nCOV-2019 from researchers across the world since December 2019.
T45 6894-7163 Sentence denotes The latest report by the GISAID database on June 2020 has shown 25 different variants of RBD from strains of nCOV-2019 collected from different countries along with the number of occurrences in these regions which is listed below for the seven most occurring mutations:
T46 7164-7472 Sentence denotes 213x N439K (211 Scotland, England, and Romania), 65x T478I in England, 30x V483A (26 USA/WA, 2 USA/UN, USA/CT, and England), 10x G476S (8 USA/WA, USA/OR, and Belgium), 7x S494P (3 USA/MI, England, Spain, India, and Sweden), 5x V483F (4x Spain and England), and 4x A475V (2 USA/AZ, USA/NY, and Australia/NSW).
T47 7473-7572 Sentence denotes It is not known whether these mutations are linked to the severity of coronavirus in these regions.
T48 7573-7796 Sentence denotes Starr and co-workers25 performed a deep mutational scanning of nCOV-2019 RBD and used flow cytometry to measure the effect of single mutations on the expression of the folded protein as well as its binding affinity to ACE2.
T49 7797-7937 Sentence denotes They showed that RBD is very tolerant to these mutations to maintain its expression level as well as binding affinity to ACE2 in most cases.
T50 7938-8053 Sentence denotes According to their results, most natural mutations exert similar binding affinities to ACE2 as wild-type nCOV-2019.
T51 8054-8287 Sentence denotes Furthermore, they showed that mutations at critical positions at the RBD-ACE2 interface at nCOV-2019 such as residues Q493 and Q498 do not reduce the binding affinity to ACE2 which shows the substantial plasticity of the interface.25
T52 8288-8477 Sentence denotes Different groups have computationally studied the binding of nCOV-2019 RBD with ACE2.25−29 All these studies point to the higher binding affinity of nCOV-2019 RBD than SARS-COV RBD to ACE2.
T53 8478-8824 Sentence denotes Interestingly, the role of water-mediated interactions has been pointed out to be a driving force which is shown to be similar for both SARS-COV and nCOV-2019 RBD.27 Spinello and co-workers30 studied the binding of nCOV-2019 and SARS-COV RBD to ACE2 and found that the former binds its receptor with 30 kcal/mol higher affinity than SARS-COV RBD.
T54 8825-8991 Sentence denotes Gao et al.31 used free energy perturbation (FEP) and showed that most amino acid mutations at the RBM from SARS-COV to nCOV-2019 increase the affinity of RBD to ACE2.
T55 8992-9274 Sentence denotes The focus of this article is to elucidate the differences between the interface of SARS-COV and nCOV-2019 with ACE2 to understand with atomic resolution the interaction mechanism and hotspot residues at the RBD/ACE2 interface using long-timescale molecular dynamics (MD) simulation.
T56 9275-9463 Sentence denotes An alanine-scanning mutagenesis in the RBM of nCOV-2019 helped to identify the key residues in the interaction, which could be used as potential pharmacophores for future drug development.
T57 9464-9644 Sentence denotes Furthermore, we performed molecular simulations on the seven most common mutations found from the surveillance of RBD mutations N439K, T478I, V483A, G476S, S494P, V483F, and A475V.
T58 9645-9790 Sentence denotes From an evolutionary perspective this study shows the residues in which the virus might further evolve to be even more dangerous to human health.