Email Alert | RSS

Journal of Peking University (Health Sciences) ›› 2021, Vol. 53 ›› Issue (1): 150-158. doi: 10.19723/j.issn.1671-167X.2021.01.023

Previous Articles     Next Articles

Homologous modeling and binding ability analysis of Spike protein after point mutation of severe acute respiratory syndrome coronavirus 2 to receptor proteins and potential antiviral drugs

CAO Ze,WANG Le-tong,LIU Zhen-ming()   

  1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, China
  • Received:2020-07-06 Online:2021-02-18 Published:2021-02-07
  • Contact: Zhen-ming LIU E-mail:zmliu@bjmu.edu.cn

RICH HTML

 16   

PDF (PC)

109

Abstract:

Objective: To explore the natural mutations in Spike protein (S protein) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the changes of affinity between virus and associated receptors or drug molecules before and after the mutation based on whole length sequencing results.Methods: In the study, the bioinformatics analysis of all the published sequences of SARS-CoV-2 was conducted and thus the high frequency mutation sites were affirmed. Taking advantages of PolyPhen-2, the functional influence of each mutation in S protein was prospected. The 3D homologous modelling was performed by SWISS-MODEL to establish mutated S protein structural model, in which the protein-docking was then implemented with angiotensin-converting enzyme 2 (ACE2), dipeptidyl peptidase-4 (DPP4) and aminopeptidase N (APN) by ZDOCK, and the combining capacity of each mutated S protein evaluated by FiPD. Finally, the binding ability between mutated S proteins and anti-virus drugs were prospected and evaluated through AutoDock-Chimera 1.14.Results: The mutations in specific region of S protein had greater tendency to destroy the S protein function by analysis of mutated S protein structure. Protein-receptor docking analysis between naturally mutated S protein and host receptors showed that, in the case of spontaneous mutation, the binding ability of S protein to ACE2 tended to be weakened, while the binding ability of DPP4 tended to be enhanced, and there was no significant change in the binding ability of APN. According to the computational simulation results of affinity binding between small molecular drugs and S protein, the affinity of aplaviroc with S protein was significantly higher than that of other small molecule drug candidates.Conclusion: The region from 400-1 100 amino acid in S protein of SARS-CoV-2 is the mutation sensitive part during natural state, which was more potential to mutate than other part in S protein during natural state. The mutated SARS-CoV-2 might tend to target human cells with DPP4 as a new receptor rather than keep ACE2 as its unique receptor for human infection. At the same time, aplaviroc, which was used for the treatment of human immunodeficiency virus (HIV) infection, may become a new promising treatment for SARS-CoV-2 and could be a potential choice for the development of SARS-CoV-2 drugs.

Key words: SARS-CoV-2, Spike glycoprotein, coronavirus, Mutation, Sequence alignment, Molecular docking simulation

CLC Number: 

  • R373.19

Table 1

Analysis of S protein mutation sites"

Nucleotide locus Amino acid mutation type Base mutation type Numbers Mutation possibility
21 750 S63V C-A 5 1.1%
21 644 Y28N T-A 3 0.7%
21 646 Y28stop C-A 6 1.4%
21 575 L5I C-A 6 1.4%
21 724 L54F G-T 3 0.7%
21 783 N74I/T/S A-I 7 1.6%
21 846 T95N C-A 6 1.4%
21 850 E96D G-T 5 1.1%
21 893 D111Y G-T 4 0.9%
21 950 V130F G-T 7 1.6%
22 033 F157L C-A 6 1.4%
22 104 G181V G-T 3 0.7%
22 207 D215E T-A/G 7 1.6%
22 432 D290E C-A 4 0.9%
22 604 A348S G-T 4 0.9%
22 606 A340A A-I 3 0.7%
22 984 Q474H G-T 6 1.4%
22 988 G476C G-T 4 0.9%
23 010 V483D/G T-A/G 5 1.1%
23 403 D614V/A/G A-I 3 0.7%
23 730 T723N C-A 4 0.9%
23 952 F797Y/C T-A/G 7 1.6%
24 022 D820E T-A/G 9 2.1%
24 034 N824K C-A 7 1.6%
24 325 K921N A-I 2 0.5%
24 368 D936Y G-T 5 1.1%
24 694 G1044G A-I 3 0.7%
24 795 A1078D C-A 6 1.4%
25 064 D1168Y G-T 7 1.6%
25 094 N1178D/H/Y A-I 4 0.9%
25 337 D1259Y G-T 6 1.4%
25 335 E1258D A-I 7 1.6%
25 336 E1258V/A/G A-I 3 0.7%

Figure 1

Possibility analysis of S protein point mutation affecting the overall structure"

Figure 2

Structure of mutation site of Spike protein before and after the point mutation A, Y28H; B, D111N; C, A348N; D, D614G; E, T723I; F, F797S; G, D936N; H, A1078V. Because of the existence of synonymous mutations and the cleavage of mutation sites in mature proteins, 33 high-frequency mutation sites eventually produced only 8 kinds of sequence changes in mature spike proteins."

Figure 3

Changes in the affinity of S protein with ACE2, DPP4, and APN receptors after mutation A, the absolute strength of binding ability of each receptor to the mutant protein, indicating that ACE2 receptor has the strongest binding ability to all mutant S protein. B, C, and D represents the percentage of changes in S protein’s binding ability to ACE2, APN, and DPP4 receptors respectively after mutation. The green part represents the changes in binding ability after mutation. The green part on the left indicates that the mutation leads to reduced binding ability; the green part on the right indicates that the mutation leads to increased binding ability. ACE2, angiotensin-converting enzyme 2; DPP4, dipeptidyl peptidase-4; APN, aminopeptidase N. AS, QH, VD, VG, and GC represent the mutation of A384S, Q474H, V483D, V483G, and G476C, respectively."

Figure 4

Schematic diagram of protein structure. A, the 3D modeling structure diagram of S protein; B, C, D, the protein structure diagrams of ACE2, DPP4, and APN, respectively; E, the structural diagram of RBD region of S protein; F, G, H, the 3D modeling structure diagrams of ACE2, DPP4, and APN, respectively binding complex with RBD region. ACE2, angiotensin-converting enzyme 2; DPP4, dipeptidyl peptidase-4; APN, aminopeptidase N; RBD, receptor binding domain."

Table 2

Cluster analysis of the binding ability of ACE2, DPP4, and APN receptors to each mutant RBD of S protein"

Mutation type ACE2 cluster DPP4 cluster APN cluster Mutation type ACE2 cluster DPP4 cluster APN cluster
AS 1 1 1 QH 2 2 2
AS-GC 2 2 2 QH-GC 1 3 2
AS-QH 1 3 3 QH-VD 1 3 3
AS-QH-GC 2 3 3 QH-VD-GC 1 2 2
AS-QH-VD 3 3 2 QH-VG 1 1 1
AS-QH-VD-GC 1 3 3 QH-VG-GC 2 3 3
AS-QH-VG 2 1 1 VD 1 1 1
AS-VD 1 2 1 VG 1 3 1
AS-VD-GC 1 2 1 Cluster 1 number 14 5 8
AS-VG 1 1 1 Cluster 2 number 7 8 8
AS-VG-GC 2 3 3 Cluster 3 number 2 10 7
AS-VG-QH-GC 2 3 3 Cluster 1 center -77.04 -121.57 -101.25
GC 1 2 2 Cluster 2 center 97.01 14.84 18.77
GC-VD 1 2 2 Cluster 3 center 385.64 190.30 226.15
GC-VG 3 2 2

Figure 5

Data analysis of the combination of small molecule drugs with RBD of S protein A, the binding free energy of various small molecule drugs with various mutant RBD. The smaller the binding free energy is, the easier the binding is. Aplaviroc has the strongest binding ability with various mutant subtypes. B-F, represents the schematic diagram of 3D modeling and analysis in cinanserin, aplaviroc, vicriviroc, obatoclax, and curcumin combined with RBD, respectively. 1 kcal=4.186 8 kJ. Abbreviations as in Figure 3."

[1] Liu J, Zheng X, Tong Q, et al. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human patho-genic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV[J]. J Med Virol, 2020,92(5):491-494.
doi: 10.1002/jmv.25709 pmid: 32056249
[2] Wang C, Liu Z, Chen Z, et al. The establishment of reference sequence for SARS-CoV-2 and variation analysis[J]. J Med Virol, 2020,10(1002):25762.
[3] Ma Y, Wu L, Shaw N, et al. Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex[J]. Proc Natl Acad Sci USA, 2015,112(30):9436-9441.
doi: 10.1073/pnas.1508686112 pmid: 26159422
[4] Kim D, Lee JY, Yang JS, et al. The architecture of SARS-CoV-2 transcriptome[J]. Cell, 2020,181(4):914-921.
doi: 10.1016/j.cell.2020.04.011 pmid: 32330414
[5] Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding[J]. Lancet, 2020,395(10224):565-574.
doi: 10.1016/S0140-6736(20)30251-8 pmid: 32007145
[6] Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin[J]. Nature, 2020,579(7798):270-273.
doi: 10.1038/s41586-020-2012-7 pmid: 32015507
[7] Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2[J]. Science, 2020,367(6485):1444-1448.
doi: 10.1126/science.abb2762 pmid: 32132184
[8] Walls AC, Park YJ, Tortorici MA, et al. Structure, function, and antigenicity of the SARS-CoV-2 Spike glycoprotein[J]. Cell, 2020,181(2):281-292.
doi: 10.1016/j.cell.2020.02.058 pmid: 32155444
[9] Chan CM, Chu H, Wang Y, et al. Carcinoembryonic antigen-related cell adhesion molecule 5 is an important surface attachment factor that facilitates entry of Middle East respiratory syndrome coronavirus[J]. J Virol, 2016,90(20):9114-9127.
doi: 10.1128/JVI.01133-16 pmid: 27489282
[10] Cui J, Li F, Shi ZL. Origin and evolution of pathogenic corona-viruses[J]. Nat Rev Microbiol, 2019,17(3):181-192.
doi: 10.1038/s41579-018-0118-9 pmid: 30531947
[11] Chu H, Chan CM, Zhang X, et al. Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells[J]. J Biol Chem, 2018,293(30):11709-11726.
doi: 10.1074/jbc.RA118.001897 pmid: 29887526
[12] Satija N, Lal SK. The molecular biology of SARS coronavirus[J]. Ann N Y Acad Sci, 2007,1102(1):26-38.
doi: 10.1196/annals.1408.002
[13] Chen L, Gui C, Luo X, et al. Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro[J]. J Virol, 2005,79(11):7095-7103.
doi: 10.1128/JVI.79.11.7095-7103.2005 pmid: 15890949
[14] Emmelkamp JM, Rockstroh JK. CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions: review of the literature[J]. Eur J Med Res, 2007,12(9):409-417.
pmid: 17933722
[15] Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells[J]. Cell Stem Cell, 2013,12(3):329-341.
doi: 10.1016/j.stem.2012.12.013
[16] Andersen PI, Krpina K, Ianevski A, et al. Novel antiviral activities of obatoclax, emetine, niclosamide, brequinar, and homoharringtonine[J]. Viruses, 2019,11(10):964.
doi: 10.3390/v11100964
[17] Wen CC, Kuo YH, Jan JT, et al. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus[J]. J Med Chem, 2007,50(17):4087-4095.
doi: 10.1021/jm070295s pmid: 17663539
[18] Aliyari Serej Z, Ebrahimi Kalan A, Mehdipour A, et al. Regulation and roles of CD26/DPPIV in hematopoiesis and diseases[J]. Biomed Pharmacother, 2017,91:88-94.
doi: 10.1016/j.biopha.2017.04.074 pmid: 28448874
[19] Cheng F, Yuan G, He J, et al. Dysregulation of DPP4 is associa-ted with the AMPK/JAK2/STAT3 pathway in adipocytes under insulin resistance status and liraglutide intervention[J]. Diabetes Metab Syndr Obes, 2019,12:2635-2644.
doi: 10.2147/DMSO.S229838 pmid: 31849507
[20] Song Z, Xu Y, Bao L, et al. From SARS to MERS, thrusting coronaviruses into the spotlight[J]. Viruses, 2019,11(1):59.
doi: 10.3390/v11010059
[21] Li Y, Zhang Z, Yang L, et al. The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 Spike[J]. iScience, 2020,23(6):101160.
doi: 10.1016/j.isci.2020.101160 pmid: 32405622
[22] Nichols WG, Steel HM, Bonny T, et al. Hepatotoxicity observed in clinical trials of aplaviroc[J]. Antimicrob Agents Chemother, 2008,52(3):858-865.
doi: 10.1128/AAC.00821-07 pmid: 18070967
[23] Kitrinos KM, Amrine-Madsen H, Irlbeck DM, et al. Virologic failure in therapy-naive subjects on aplaviroc plus lopinavir-ritonavir: detection of aplaviroc resistance requires clonal analysis of envelope[J]. Antimicrob Agents Chemother, 2009,53(3):1124-1131.
doi: 10.1128/AAC.01057-08 pmid: 19075068
[1] FENG Ke,NI Jing-jing,XIA Yan-qing,QU Xiao-wei,ZHANG Hui-juan,WAN Feng,HONG Kai,ZHANG Cui-lian,GUO Hai-bin. Genetic analysis of three cases of acephalic spermatozoa syndrome caused by SUN5 mutation and the outcome of assisted reproductive technology [J]. Journal of Peking University (Health Sciences), 2021, 53(4): 803-807.
[2] YANG Lin-cheng,ZHANG Rui-tao,GUO Li-jun,XIAO Han,ZU Ling-yun,ZHANG You-yi,CHENG Qin,ZHAO Zhi-ling,GE Qing-gang,GAO Wei. Hypoxia and inflammation are risk factors for acute myocardial injury in patients with coronavirus disease 2019 [J]. Journal of Peking University (Health Sciences), 2021, 53(1): 159-166.
[3] WU Jun-yi,YU Miao,SUN Shi-chen,FAN Zhuang-zhuang,ZHENG Jing-lei,ZHANG Liu-tao,FENG Hai-lan,LIU Yang,HAN Dong. Detection of EDA gene mutation and phenotypic analysis in patients with hypohidrotic ectodermal dysplasia [J]. Journal of Peking University (Health Sciences), 2021, 53(1): 24-33.
[4] Fang BAO,Wei-li SHI,Jing HU,Di ZHANG,Dong-han GAO,Yun-xia XIA,Hong-mei JING,Xiao-yan KE,Qing-gang GE,Ning SHEN. Analysis of the correlation between lymphocyte subsets and severity of corona virus disease 19 [J]. Journal of Peking University (Health Sciences), 2020, 52(6): 1075-1081.
[5] Yi BAO,Juan-fen MO. Concordant point mutation of ETS-related gene (ERG) in tumor tissues from a synchronous multiple primary lung cancer: A case report [J]. Journal of Peking University (Health Sciences), 2020, 52(5): 971-974.
[6] Xiao-ning YUAN,Qing-yang MENG,Ning SHEN,Yu-xuan LI,Chao LIANG,Man CUI,Qing-gang GE,Xiao-guang LI,Kun TAN,Qian CHEN,Jing WANG,Xiao-yong ZENG. Detection and evaluation of SARS-CoV-2 nucleic acid contamination in corona virus disease 19 ward surroundings and the surface of medical staff’s protective equipment [J]. Journal of Peking University (Health Sciences), 2020, 52(5): 803-808.
[7] Qiu WANG,Jin-yu GUO,Hong SUN,Ling WANG,Ju-su YING,Hui-xin LIU. Investigation of protective exposure risk events in nurses against corona virus disease 2019 in Wuhan [J]. Journal of Peking University (Health Sciences), 2020, 52(4): 711-714.
[8] Zhu YOU,Li-li XU,Xue-fen LI,Jian-yun ZHANG,Jing DU,Li-sha SUN. BRAF gene mutations in ameloblastic fibromas [J]. Journal of Peking University(Health Sciences), 2019, 51(1): 4-5.
[9] Hao WANG,Yang LIU,Hao-chen LIU,Dong HAN,Hai-lan FENG. Detection and functional analysis of BMP2 gene mutation in patients with tooth agenesis [J]. Journal of Peking University(Health Sciences), 2019, 51(1): 9-15.
[10] Rui LIU,Jia-yu ZHAI,Xiang-yuan LIU,Zhong-qiang YAO. Progressive pseudorheumatoid dysplasia misdiagnosed asankylosing spondylitis: a case report [J]. Journal of Peking University(Health Sciences), 2018, 50(6): 1112-1116.
[11] ZHANG Xiao-dong, LIU De-ruo. Correlation between the new lung adenocarcinoma classification and epidermal growth factor receptor mutation [J]. Journal of Peking University(Health Sciences), 2018, 50(4): 640-644.
[12] YANG Xi-ying, ZHU Ling-ping, LIU Xue-qin, ZHANG Chun-yu, YAO Yong, WU Ye. Genetic diagnosis of Caroli syndrome with autosomal recessive polycystic kidney disease: a case report and literature review [J]. Journal of Peking University(Health Sciences), 2018, 50(2): 335-339.
[13] SIMA Zi-han, HONG Ying-ying, LI Tie-jun△. Effects of PTCH1 mutations on the epithelial proliferation derived from keratocystic odontogenic tumour [J]. Journal of Peking University(Health Sciences), 2017, 49(3): 522-526.
[14] HE Hui-ying， LIU Yang， HAN Dong， LIU Hao-chen， BAI Bao-jing, FENG Hai-lan. EDA mutation screening and phenotype analysis in patients with tooth agenesis [J]. Journal of Peking University(Health Sciences), 2016, 48(4): 686-691.
[15] MA Xiao-mei, CAO Yan-zhen, JI Wen-li, ZHAO Feng, FANG Xin-zhi. Analysis of epidermal growth factor receptor mutations and its clinico-pathologic characteristics of the primary lung adenocarcinoma in Xinjiang Uighur Autonomous Region [J]. Journal of Peking University(Health Sciences), 2016, 48(4): 663-666.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] . [J]. Journal of Peking University(Health Sciences), 2009, 41(4): 456 -458 .
[2] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 125 -128 .
[3] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 135 -140 .
[4] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 158 -161 .
[5] . [J]. Journal of Peking University(Health Sciences), 2009, 41(2): 217 -220 .
[6] . [J]. Journal of Peking University(Health Sciences), 2009, 41(1): 52 -55 .
[7] . [J]. Journal of Peking University(Health Sciences), 2009, 41(1): 109 -111 .
[8] . [J]. Journal of Peking University(Health Sciences), 2009, 41(3): 297 -301 .
[9] . [J]. Journal of Peking University(Health Sciences), 2009, 41(5): 599 -601 .
[10] . [J]. Journal of Peking University(Health Sciences), 2009, 41(5): 516 -520 .
Copyright © Journal of Peking University (Health Sciences), All Rights Reserved.
Powered by Beijing Magtech Co. Ltd