Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico

In this Journal we previously reported the predicted SARS-CoV-2 spike-host cell receptor GRP78 binding site (1Ibrahim I.M. Abdelmalek D.H. Elshahat M.E. Elfiky A.A. COVID-19 prediction.J Infect. 2020; 80: 554-562Abstract Full Text PDF PubMed Scopus (343) Google Scholar). New variant VUI 202,012/01 started in UK and currently spreading Europe Australia during last few days. The new bears about nine mutations spike protein (Δ69–70, Δ145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H). N501Y lies receptor-binding domain (RBD) of interacts with host-cell ACE2 responsible for viral recognition entry. We tried to simulate system ACE2-SARS-CoV-2 RBD wildtype mutated isoform (N501Y). Additionally, association is modeled at presence mutant spike. Based on our previous study, Heat Shock Protein A5 (HSPA5), also called, Glucose Regulated 78 (GRP78) or Bip, bind Spike.1Ibrahim Scholar Spike alongside putative receptor, Angiotensin-Converting Enzyme 2 (ACE2).2Elfiky Ibrahim Ismail A.M. Elshemey W.M. A possible role cross vaccination against COVID-19.J Abstract (11) Scholar,3Elfiky spike-heat shock may be related immersed human coronaviruses.Front Pharmacol. 11577467Crossref (28) spike/ACE2 complex using HADDOCK 2.4 webserver4van Dijk A.D. Bonvin Solvated docking: introducing water into modelling biomolecular complexes.Bioinformatics. 2006; 22: 2340-2347Crossref (124) (Fig. 1A). PyMOL V2.2.2 was utilized do a point mutation (N501Y) resemble found COVID-19.52.4.1VThe Molecular Graphics System, Version 2.4.1. LLC, Schrödinger2020Google docked both wild type RBD-ACE2 (WT ACE2-RBD), (Mut ACE2-RBD). RBD's active sites were T428, V429, V432, T434, F451, S452, V457 & I489 C480-C488, respectively, rest options kept as default. carbohydrate moieties (NAG) attached proteins held structure. score values WT ACE2-RBD Mut are −74.3 ± 0.9 −95.6 1.0, respectively. This indicates better than complexes. There 28.7% increase form compared ACE2-RBD. interactions between two complexes presented Table 1. tightly bound three H-bonds five hydrophobic contacts instead case ACE2-RBD, On other hand, docking scores established upon isoforms shown 1.Table 1The interaction patterns after Bold residues interacting complexes, while blue Pi-stacking interactions.H-bondingHydrophobic interactionSalt BridgecomplexHADDOCK scoreNo.Amino acids involved from RBDAmino GRP78No.Amino GRP78WT ACE2-RBD-GRP78−74.3 0.92N481 F486E427 G4543T478, P479, V483V453 (2) V457Mut ACE2-RBD-GRP78−95.6 1.03E471, T478, F486G430, G4545P479, N481, V483 (2), F486T428, V453 V457, V490complexHADDOCK ACE2No.Amino ACE2WT ACE2-RBD−126.1 3.312K417, Y449, Y473, N487, Y489, Q493, S494, T500(3), G502, V503E23, D30, H34(2), D38, Y41, Y83(2), T324, K353, D355, R3579F456(2), A475, F486(2), T500(2)Q24, T27(3), M82, Y83, D3551E484K31Mut ACE2-RBD−120.8 1.713K417, G446, Y453, N487(3), F490, Q498(2), T500, Y501Q24, T27, K31(2), H34, Q42(4), R3578F456(2), F486(3), F500, Y501, Y505T27(2), K31, K3531E484K31 Open table tab As table, almost same. through dozen H-bonds, eight contacts, salt bridge. Y501 spike's engaged H-bond K353 formed π-stacking Y41 ACE2. best result experiments (GRP78 ACE2-RBD) selected Dynamic Simulation (MDS) Nanoscale molecular dynamics software (NAMD) version 2.13.6Phillips J.C. Braun R. Wang W. Gumbart J. Tajkhorshid E. Villa et al.Scalable NAMD.J Comput Chem. 2005; 26: 1781-1802Crossref (13350) necessary files MDS generated CHARMM-GUI webserver. system's temperature concentration set 310 K 0.154 M NaCl physiological conditions. minimized 20,000 steps constant number atoms, volume, (NVT) ensemble conjugate gradient algorithm. then equilibrated pressure, (NPT) one nanosecond period. pressure controlled by Nose-Hoover Langevin piston atmospheric (1.01325 bar), control temperature. Finally, production run 25 ns initialized NVT ensemble. force field used CHARMM36 parameters. TIP3P model simulation NAMD 2.13 software.7Mark P. Nilsson L. Structure TIP3P, SPC, SPC/E models 298K.J Phys Chem A. 2001; 105: 9954-9960Crossref (1958) Different in-house scripts visualizing (VMD) tools analyze data.8Humphrey Dalke Schulten K. VMD: visual dynamics.J Mol Graph. 1996; 14 (33-8): 27-28Crossref (39890) Scholar,9Elfiky Recognition gluconeogenic enzymes; Icl1, Fbp1, Mdh2 Gid4 ligase: study.J Recognit. 33: e2831Crossref (4) Fig. 1B shows superposition per-residue Root Mean Square Fluctuations Å (calculated MDS) ACE2-RBD-GRP78 (blue line) (orange line). show highly flexible regions asterisks) cartoon), no significant differences. systems need more in-depth analysis calculations that require time. letter, propose shed light effect host cell-surface GRP78. can targeted peptides, antibodies, phytochemicals (10Elfiky Baghdady Ali S.A. Ahmed M.I. targeting: hitting birds stone.Life Sci. 260118317Crossref (52) All authors declare competing interest work. A.E. own research idea, wrote manuscript, draw figures, I.I. performed make tables. approve final manuscript. Cairo University supported work grant.