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Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease

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Science Advances  11 Sep 2020:
Vol. 6, no. 37, eabd0345
DOI: 10.1126/sciadv.abd0345

Figures

  • Fig. 1 Structure of Mpro and density maps of ebselen binding.

    (A) Mpro dimer and (B) protomer A (top view). In both panels, Mpro domains I, II, and III are shown in red, blue, and gray, respectively. Cys145 and His41 (the catalytic dyad) are shown in cyan. Yellow surfaces show the most probable interaction sites between Mpro and ebselen (highest probability density). The loop (residues 185 to 201) connecting domains I and II with domain III is shown in pink (B). The inset shows the chemical structure of the ebselen molecule.

  • Fig. 2 Binding modes for ebselen-Mpro complexes.

    (A) At the catalytic site and (B) at the intersection between domains II and III. In both panels, ebselen, as well as main residues displaying contacts, is shown in sticks.

  • Fig. 3 Strain analysis of ebselen-Mpro complexes.

    (A) β factor, estimated from the root mean squared fluctuation. (B) Shear strains. In both upper panels, Mpro-apo results are shown in green (Mpro-apo); for ebselen, when bound to the catalytic site (Mpro-Eb-Cat), results are in red. For the domain II–III interface (Mpro-Eb-Domain), results are shown in blue. For two ebselen molecules bound at both sites simultaneously (Mpro-Eb-Cat-Domain), results are shown in black. For the shear strain calculation, only the Cα atoms are included. (C) Shear strains mapped onto the different protein complexes from (B). The redder the region and the larger the radius of the structure, the higher the shear strain. For clarity, only the catalytic site and domains I and II are shown, the drug is shown as spheres, and the catalytic dyad is shown as blue sticks.

  • Fig. 4 Close-up of the highly strained regions identified from strain analysis.

    (A) The Mpro structure with ebselen molecules bound to both catalytic site and domains II and III interface simultaneously. In the upper panel, Lys137 and Phe140 are shown as sticks. The lower panel shows the close-up of this region and shows the backbone H-bond between Lys137 and Phe140 at the beginning and end of the simulation. (B) The Mpro structure with ebselen bound to the domains II and III interface. The close-up shows that a hydrogen bonding interaction is formed with Gln107 side chain, and hydrophobic contacts are formed with His246, Val202, Ile249, Phe294, Pro132, and Ile200. This last residue is located at the end of the 185–201 loop, which connects domain III with domains I and II (catalytic site). In both (A) and (B) upper panels, ebselen is shown as spheres and the catalytic dyad as magenta sticks.

  • Fig. 5 Water analysis of Mpro complexes.

    Top: Water inlet clusters for (A) apo protein and (B) ebselen in domains II and III. The biggest cluster in both cases is divided into three parts using K-means (24) and colored for clarity. Bottom: MAV (as light green surface) and hotspots (blue-red color and sphere radius relative to occupation values) for (A) apo and (B) ebselen in domains II and III. The catalytic dyad is represented with sticks (magenta, His41; cyan, Cys145).

Tables

  • Table 1 Absolute binding free energy for Mpro-ebselen complexes.

    The average and uncertainty energy values were obtained from three independent replicas for each site. Details of the calculation are described in Materials and Methods.

    Binding siteAbsolute binding free energy
    (kcal/mol)
    Catalytic site−5.55 ± 2.28
    Domains II and III site−8.87 ± 1.59

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