LitCovid-sentences  

PMC:7605337 / 40492-57691 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T277 0-10 Sentence denotes Discussion
T278 11-164 Sentence denotes In this work, we preformed MD simulations to unveil the detailed molecular mechanism for the receptor binding of nCOV-2019 and compared it with SARS-COV.
T279 165-277 Sentence denotes The role of key residues at the interface of nCOV-2019 with ACE2 was investigated by computational ala-scanning.
T280 278-444 Sentence denotes A rigorous 500 ns MD simulation was performed for nCOV-2019, SARS-COV, and few mutants (Y449, T478I, Y489A, and S494P) as well as 300 ns MD simulation on each mutant.
T281 445-662 Sentence denotes These simulations aid in understanding the dynamic role of RBD/ACE2 interface residues and estimating the binding free energy of these variants, which shed light on crucial residues for the RBD/ACE2 complex stability.
T282 663-975 Sentence denotes Moreover, numerous mutations have been identified in the RBD of different nCOV-2019 strains from all over the world not known to be critical for infection.54 The effect of these mutations on the stability of the RBD/ACE2 complex was investigated to shed light on their role in the viral infection of coronavirus.
T283 976-1235 Sentence denotes Changes in the RBD structure of nCOV-2019, SARS-COV, and mutants from their crystal structure were analyzed by RMSD and RMSF. nCOV-2019 showed a stable structure with a RMSD =1.5 Å, whereas SARS-COV had a larger RMSD value between 3–4 Å during the simulation.
T284 1236-1310 Sentence denotes Most mutations of nCOV-2019 maintained similar stability to the wild-type.
T285 1311-1442 Sentence denotes However, a few nCOV-2019 mutations resulted in larger deviations (>2 Å), i.e., Y489A, F456A, Y505A, N487A, K417A, Y473A, and Y449A.
T286 1443-1687 Sentence denotes We further investigated the structure of the extended loop domain (Figure 1B) and discovered that nCOV-2019 is stable with an RMSD of less than 1 Å, whereas the extended loop in SARS-COV shows an RMSD of about 3 Å during simulation (Figure S2).
T287 1688-1733 Sentence denotes Some mutants showed high RMSD in this region.
T288 1734-1813 Sentence denotes Alanine-substitution at residue N487 increased the extended loop RMSD to 2.5 Å.
T289 1814-1907 Sentence denotes Other mutations that increased the extended loop RMSD (>2 Å) include Y449A, G477A, and E484A.
T290 1908-1998 Sentence denotes The dynamic behavior of RBD was further investigated by analyzing the RMSF of all systems.
T291 1999-2074 Sentence denotes As shown in Figure 4, nCOV-2019 shows less fluctuation in L3 than SARS-COV.
T292 2075-2300 Sentence denotes This is due to the presence of a four-residue motif (GQTQ) in nCOV-2019 L3, which forces the loop to adopt a compact structure by making two H-bonds (G485-C488 and Q474-G476) and thereby reducing the fluctuations in the loop.
T293 2301-2447 Sentence denotes Residues F486 and N487 play major roles in stabilizing the recognition loop by making π-stacking and H-bond interactions with residue Y83 on ACE2.
T294 2448-2507 Sentence denotes Alanine substitution at N487 introduced a large RMSF to L1.
T295 2508-2862 Sentence denotes Mutation L472 to F486 in SARS-COV was shown to favor binding by −1.2 ± 0.2 kcal/mol using FEP.26 In addition, this mutation was shown to be among the five mutations that produce a super affinity ACE2 binder based on SARS-COV RBD.6 Alanine mutations at residues Y449, G447, and E484 increased the motion in L3 characterized by a large RMSF in this region.
T296 2863-3101 Sentence denotes Using PCA, the aFEL for nCOV-2019 and SARS-COV demonstrated that the former occupies only one low energy state whereas the latter forms two distinct low energy basins separated by a metastable state with a barrier of about 6–7.5 kcal/mol.
T297 3102-3217 Sentence denotes This confirms that the level of binding for the RBD domain is weaker in SARS-COV due to the presence of two basins.
T298 3218-3352 Sentence denotes Similarly, alanine-substitution for a few residues caused the FEL to degenerate into separate multiple low energy regions (Figure S4).
T299 3353-3531 Sentence denotes Dominant motions in the RBD are visualized in Figure S5 using the first eigenvector of the PCA. nCOV-2019 and SARS-COV did not show any strong motion in the extended loop region.
T300 3532-3701 Sentence denotes Porcupine plots of alanine-mutants demonstrated that mutant N487A shows large motion in the L1 region and Y449A, G447A, and E484A showed large motions in L3 (Figure S5).
T301 3702-3912 Sentence denotes To better characterize the functional motions of RBD, DCCM for all systems are constructed and shown in Figure 6 and Figure S6. nCOV-2019 showed a large correlation between the α4-L1- β5 and α5- L4- β5 regions.
T302 3913-4003 Sentence denotes This correlation was stronger in SARS-COV and few mutants such as Y449A, G447A, and E484A.
T303 4004-4067 Sentence denotes Another important correlation in nCOV-2019 is inside L3 and β6.
T304 4068-4199 Sentence denotes This correlation is stronger in nCOV-2019 than SARS-COV due to the presence of β6 which makes the loop to adopt correlated motions.
T305 4200-4264 Sentence denotes Few mutants impact the correlation in this region such as N487A.
T306 4265-4520 Sentence denotes Interestingly, mutant F486A which is in L3 and participates in binding by π-stacking interaction with Y83 on ACE2, disrupts the DCCM of wild-type nCOV-2019 and introduces strong correlation in the extended loop region as well as the core structure of RBD.
T307 4521-4793 Sentence denotes The details of hydrogen bond and salt-bridge pattern in nCOV-2019 and SARS-COV to ACE2 (Table 1) are key to the virus attachment to the host. nCOV-2019 residues participate in 10 H-bonds/1 salt bridge with ACE2, whereas SARS-COV only has 5 H-bonds/1 salt bridge with ACE2.
T308 4794-4911 Sentence denotes This significantly contributes to ∼30 kcal/mol difference in the total binding free energy of nCOV-2019 and SARS-COV.
T309 4912-5288 Sentence denotes The binding energies calculated here for nCOV-2019 and SARS-COV (−50.22 ± 1.93 and −18.79 ± 1.53 kcal/mol, respectively) are in good agreement with the binding energies calculated using the generalized Born method by Spinello et al.30 Moreover, the patterns of H-bonds between nCOV-2019 and ACE2 were also already characterized by other groups26,30 which agrees with our work.
T310 5289-5376 Sentence denotes An important H-bond between nCOV-2019 and ACE2 is between G502 on RBD and K353 of ACE2.
T311 5377-5456 Sentence denotes G502 is in the L4 region, which is populated by 5 H-bonds between RBD and ACE2.
T312 5457-5747 Sentence denotes The contribution of this residue to the total binding energy is −2.03 ± 0.04 kcal/mol and the Ala-substitution at G502 has the highest effect on the binding energy among all the residues by lowering the total binding affinity to 24.31 ± 2.98 kcal/mol, which is the lowest among all mutants.
T313 5748-5837 Sentence denotes This mutation breaks the other H-bonds in L4 such as H-bonds from residues Q498 and T500.
T314 5838-5961 Sentence denotes This residue is preserved and corresponds to residue G488 in SARS-COV, which also makes a H-bond with residue K353 on ACE2.
T315 5962-6073 Sentence denotes Residue Q493 in nCOV-2019 participates in binding ACE2 by making two H-bonds with residues E35 and K31 on ACE2.
T316 6074-6175 Sentence denotes Q493 corresponds to residue N479 in SARS-COV, which only makes one H-bond with residue Lys31 on ACE2.
T317 6176-6262 Sentence denotes This caused Q493 to have more contribution to total binding than its counterpart N479.
T318 6263-6477 Sentence denotes However, alanine substitution at Q493 did not affect the total binding energy and this mutant had a total binding energy similar to the wild-type complex as it maintains the number H-bonds in the wild-type complex.
T319 6478-6595 Sentence denotes Residues Q498 and T500 in nCOV-2019 are crucial for binding by making H-bonds with ACE2 residues D38, D355, and K353.
T320 6596-6709 Sentence denotes Residue Q498 corresponds to residue Y484 in SARS-COV which does not make any H-bond in the SARS-COV/ACE2 complex.
T321 6710-6843 Sentence denotes Q498 contributes to binding by −6.72 ± 0.18 kcal/mol which is more than the contribution of Y484 in SARS-COV (−1.83 ± 0.06 kcal/mol).
T322 6844-6923 Sentence denotes Ala-substitution at Q498 did not show large impact on the total binding energy.
T323 6924-7028 Sentence denotes Residue T500 is conserved and corresponds to residue T486 which also makes a H-bond with Asp355 on ACE2.
T324 7029-7106 Sentence denotes Mutation of T500 to Alanine lowers the binding affinity by about 10 kcal/mol.
T325 7107-7244 Sentence denotes Residue N487 in nCOV-2019 locates in L3 and plays a crucial role in stabilizing the recognition loop by making a H-bond with Y83 on ACE2.
T326 7245-7460 Sentence denotes This residue contributes to the total binding energy of nCOV-2019 by −1.52 ± 0.06 kcal/mol, whereas its corresponding residue in SARS-COV does not show any contribution to the binding energy (−0.02 ± 0.05 kcal/mol).
T327 7461-7601 Sentence denotes This demonstrates that L3 in SARS-COV has evolved to be an important recognition loop in nCOV-2019, which participates in binding with ACE2.
T328 7602-7755 Sentence denotes Residue K417 in nCOV-2019 has the most contribution to the total binding energy (−12.34 ± 0.23 kcal/mol by making a salt-bridge with residue D30 on ACE2.
T329 7756-7895 Sentence denotes This residue is crucial for the binding of RBD and ACE2 and alanine substitution lowers the total binding energy to −29.56 ± 2.95 kcal/mol.
T330 7896-8090 Sentence denotes This salt-bridge is found to be important for the stability of the crystal structure of the RBD/ACE2 complex in nCOV-2019.4 K417 is Val404 in SARS-COV which does not participate in binding ACE2.
T331 8091-8192 Sentence denotes Another important residue in nCOV-2019 is L455 which contributes to binding by −1.86 ± 0.03 kcal/mol.
T332 8193-8339 Sentence denotes This residue is important for hydrophobic interaction with ACE2 and mutating it to alanine lowers the total binding affinity by about 17 kcal/mol.
T333 8340-8490 Sentence denotes The hydrophobic residue F456 in nCOV-2019 also has a favorable contribution to the binding energy and F456A lowers the binding affinity by 5 kcal/mol.
T334 8491-8854 Sentence denotes These results are in fair agreement with experimental binding measurements with deep mutational scanning of RBD in nCOV-2019 where they used flow cytometry for different ACE2 concentrations to measure the dissociation constant KD.25 It was shown that mutations at K417, N487, T500, and G502 are detrimental for binding to ACE2, which agrees with the results here.
T335 8855-9126 Sentence denotes These experiments showed that mutations at Q493 and Q498 do not impact the binding affinity of RBD to ACE2 which demonstrates the high plasticity of the network of H-bonds at the interface where upon mutation at these residues the network can reshape to form new H-bonds.
T336 9127-9237 Sentence denotes Mutations at hydrophobic residues L455 and F456 are shown to reduce the binding affinity in these experiments.
T337 9238-9444 Sentence denotes The total binding energy calculation of all the variants showed that mutation Y489A has the highest binding affinity among all systems which is about 11 kcal/mol stronger than that of the nCOV-2019 complex.
T338 9445-9543 Sentence denotes This residue is located in β6, which is part of the recognition region of RBD for binding to ACE2.
T339 9544-9718 Sentence denotes Removal of this bulky hydrophobic residue at the interface with ACE2 caused the extended loop to move closer to the ACE2 interface and make more H-bonds with ACE2 (Table S3).
T340 9719-9846 Sentence denotes A high electrostatic interaction energy is the reason for the higher binding energy of mutant Y489A than the wild-type complex.
T341 9847-10038 Sentence denotes It is interesting to note that among the five residues L455, F456, Y473, A475, and Y489 that make hydrophobic interactions with ACE2, Y489 is the only residue that is conserved from SARS-COV.
T342 10039-10200 Sentence denotes However, the experimental binding affinity measurements using deep mutational scanning showed that mutations at this position lower the binding affinity to ACE2.
T343 10201-10282 Sentence denotes Other alanine substitutions that increase the binding energy are G446A and G447A.
T344 10283-10417 Sentence denotes Residues G446 and G447 reside in L1 and mutation to alanine can make L1 take a more rigid form as shown in the RMSF plot in Figure S3.
T345 10418-10751 Sentence denotes However, experiment showed that these mutations have similar or lower binding affinities to ACE2 than the wild-type RBD and care must be taken when interpreting these results.25 This discrepancy could be due to force-field inaccuracy and the deficiencies in the PBSA method for the treatment of solvent in binding energy calculation.
T346 10752-10861 Sentence denotes Further studies are needed to investigate whether these mutations will increase the binding affinity to ACE2.
T347 10862-11209 Sentence denotes Deep mutational scanning using flow cytometry is a qualitative method to measure the impact of a large number of mutations of protein–protein interactions and further experiments such as SPR or isothermal titration calorimetry which are conventional methods for measuring binding affinities needed to study the effect of these mutations in detail.
T348 11210-11324 Sentence denotes Important mutations found in naturally occurring nCOV-2019 appear to influence to some extent the binding to ACE2.
T349 11325-11486 Sentence denotes Mutation T478I which is one of the most frequent mutations according to GISAID database, increases the binding affinity of nCOV-2019 to ACE2 by about 6 kcal/mol.
T350 11487-11668 Sentence denotes Mutation N439K has the highest occurrence among all strains of coronavirus in the GISAID database which demonstrated the highest electrostatic interaction among all studied systems.
T351 11669-11771 Sentence denotes This residue corresponds to R426 in SARS-COV which exerts a salt-bridge interaction with E329 on ACE2.
T352 11772-11898 Sentence denotes Mutation N439K recovers some of this ACE2 interaction; however, it exerts a binding affinity similar to that of wild-type RBD.
T353 11899-12041 Sentence denotes Contribution of important interface residues to binding affinity was compared for mutations T478I, N439K, and wild-type nCOV-2019 (Figure S7).
T354 12042-12223 Sentence denotes The most striking differences between wild-type RBD and mutation T478I are residues Y449 and Q498 which have significantly higher contribution to binding than the wild type residue.
T355 12224-12310 Sentence denotes Most other residues at the interface have similar binding affinities to the nCOV-2019.
T356 12311-12497 Sentence denotes A higher H-bond persistence is also seen for these two residues Y449 and Q498 compared to the wild type RBD which is the reason for their higher contribution to the total binding energy.
T357 12498-12582 Sentence denotes Mutation N439K has a slightly lower binding affinity to ACE2 than the wild type RBD.
T358 12583-12850 Sentence denotes Per residue binding energy decomposition showed that K439 in this system has a favorable contribution of −1.80 ± 0.15 kcal/mol to the total binding energy which is balanced by a lower contribution of K417 which resulted in a binding affinity similar to wild-type RBD.
T359 12851-12991 Sentence denotes Mutant E484A, which is also one of the observed mutations based on GISAID database, demonstrates a high electrostatic interaction with ACE2.
T360 12992-13164 Sentence denotes E484 contributes to binding by 3.56 ± 0.15 kcal/mol whereas the corresponding residue in SARS-COV, P469 contributes to binding of SARS-COV to ACE2 by −0.27 ± 0.01 kcal/mol.
T361 13165-13252 Sentence denotes This residue is close to D30 on ACE2 and has electrostatic repulsion with this residue.
T362 13253-13596 Sentence denotes Most natural mutants including N439K, A475V, G476S, V483A, V483F, E484A, and S494P showed similar or slightly lower binding affinities to ACE2 compared to wild-type complex which agrees with experimental binding measurements.25 However, the experimental binding affinity for T478I also showed similar binding affinity to the wild-type complex.
T363 13597-13795 Sentence denotes This difference could be due to the use of MMPBSA approach for calculation of polar solvation and further studies are needed to study the effect of this mutation on viral infectivity of coronavirus.
T364 13796-13886 Sentence denotes Additional sequence differences between nCOV-2019 and SARS-COV influence RBD/ACE2 binding.
T365 13887-14087 Sentence denotes Residue D480 in SARS-COV contributes negatively to total binding energy (6.25 ± 0.14 kcal/mol) and mutating this residue to S494 in nCOV-2019 lowers this negative contribution to 1.17 ± 0.06 kcal/mol.
T366 14088-14192 Sentence denotes D480 in SARS-COV is located in a region of high negative charge from residues E35, E37, and D38 on ACE2.
T367 14193-14368 Sentence denotes Electrostatic repulsion between D480 on SARS-COV and the acidic residues on ACE2 is the reason for highly negative contribution of this residue to binding of SARS-COV to ACE2.
T368 14369-14445 Sentence denotes Mutation to S494 in this location removes this highly negative contribution.
T369 14446-14608 Sentence denotes Gao and co-workers26 computed the relative free energies of binding because of mutations from the RBD-ACE2 of SARS-COV to the corresponding residues in nCOV-2019.
T370 14609-14767 Sentence denotes They used a FEP approach and showed that mutation D480S in SARS-COV changed the binding free energy by −1.9 ± 0.8 kcal/mol which is consistent with our study.
T371 14768-14989 Sentence denotes Furthermore, we performed an additional simulation on D480A mutant in SARS-COV and found that this mutation has a binding affinity of 23.46 ± 3.07 kcal/mol which is about 5 kcal/mol higher than the wild-type SARS-COV RBD.
T372 14990-15175 Sentence denotes In addition, experimental binding affinity measurements showed that mutations of S494 to an acidic residue highly reduce the binding affinity to ACE2 which confirms the hypothesis here.
T373 15176-15302 Sentence denotes To our knowledge this is first detailed molecular simulation study on the effect of mutations on binding of nCOV-2019 to ACE2.
T374 15303-15876 Sentence denotes Previous computational studies have found that nCOV-2019 binds to ACE2 with a total binding affinity which was about 30 kcal/mol stronger than SARS-COV and is in fair agreement with the results here.56 The critical role of interface residues is computationally investigated here and in other articles and the results of all the studies indicate the importance of these residues for the stability of the complex and finding hotspot residues for the interaction with receptor ACE2.26,30,55,56 It is interesting to note the role of L3 in the stability of the RBD/ACE2 complex.
T375 15877-16007 Sentence denotes The amino acid insertions in L3 for nCOV-2019 have converted an unessential part of RBD in SARS to a functional domain of the RBD.
T376 16008-16163 Sentence denotes This loop participates in binding ACE2 by making H-bond as well as π-stacking interactions with ACE2, which makes this region to act as a recognition loop.
T377 16164-16463 Sentence denotes Previous studies on SARS-COV have shown that there is a correlation between the higher binding affinity to the receptor and higher infection rate by coronavirus.6,13,57 The higher binding affinity of nCOV-2019 for ACE2 than SARS-COV to ACE2 is suggested to be the reason for its high infection rate.
T378 16464-16640 Sentence denotes Most natural mutations showed similar binding affinities to wild-type ACE2 which indicates that the virus was already effective at the beginning of the crisis for binding ACE2.
T379 16641-16732 Sentence denotes A few mutations such as N489A and T478I are shown to increase the binding affinity to ACE2.
T380 16733-16821 Sentence denotes However, more studies are needed to investigate the effect of these mutations in detail.
T381 16822-17012 Sentence denotes Mutations of nCOV-2019 RBD that do not change the binding affinity and complex stability could have implications for antibody design purposes since they could act as antibody escape mutants.
T382 17013-17199 Sentence denotes Escape from monoclonal antibodies is observed for mutations of SARS-COV in 2002 and these mutations should be considered for any antibody design endeavors against these escape mutations.