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. 2022 Sep 3;23(17):10088.
doi: 10.3390/ijms231710088.

Quantum Biochemistry and MM-PBSA Description of the ZIKV NS2B-NS3 Protease: Insights into the Binding Interactions beyond the Catalytic Triad Pocket

Valdir Ferreira de Paula Junior  1 , Mauricio Fraga van Tilburg  1 , Pablo Abreu Morais  2 , Francisco Franciné Maia Júnior  3 , Elza Gadelha Lima  4 , Victor Tabosa Dos Santos Oliveira  4 , Maria Izabel Florindo Guedes  1 , Ewerton Wagner Santos Caetano  5 , Valder Nogueira Freire  6
Affiliations

Quantum Biochemistry and MM-PBSA Description of the ZIKV NS2B-NS3 Protease: Insights into the Binding Interactions beyond the Catalytic Triad Pocket

Valdir Ferreira de Paula Junior et al. Int J Mol Sci. .

Abstract

The Zika virus protease NS2B-NS3 has a binding site formed with the participation of a H51-D75-S135 triad presenting two forms, active and inactive. Studies suggest that the inactive conformation is a good target for the design of inhibitors. In this paper, we evaluated the co-crystallized structures of the protease with the inhibitors benzoic acid (5YOD) and benzimidazole-1-ylmethanol (5H4I). We applied a protocol consisting of two steps: first, classical molecular mechanics energy minimization followed by classical molecular dynamics were performed, obtaining stabilized molecular geometries; second, the optimized/relaxed geometries were used in quantum biochemistry and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) calculations to estimate the ligand interactions with each amino acid residue of the binding pocket. We show that the quantum-level results identified essential residues for the stabilization of the 5YOD and 5H4I complexes after classical energy minimization, matching previously published experimental data. The same success, however, was not observed for the MM-PBSA simulations. The application of quantum biochemistry methods seems to be more promising for the design of novel inhibitors acting on NS2B-NS3.

Keywords: MM-PBSA; NS2B-NS3; Zika virus; oxyanion orifice; quantum biochemistry.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representation of the oxyanion orifice of NS2B in the open state coupled to NS3 PDB ID: 5GJ4 (A), and in the closed state coupled with a PDB ID: 5H4I inhibitor (B). Overlapping of NS3 structures showing how the geometry of the oxyanion orifice changes (C).
Figure 2
Figure 2
(A) Superimposition of the Zika virus protease co-crystallized with inhibitors benzoic acid (BC, 5YOD PDB file, emerald color) and benzimidazole-1-ylmethanol (B1Y, 5H4I PDB file, mustard color) at the active site; (B) BC in 5YOD; (C) B1Y in 5H4I; (D,E) 2D representation of BC and B1Y; (F) alignment of the viral proteases according to the 5YOD and 5H4I PDB files.
Figure 3
Figure 3
Molecular dynamics simulation of the BC:5YOD structure in water: (A) Cα RMSD; (B) Cα RMSF; (C) RMSD of BC relative to the protease; (D) BC position in the co-crystallized structure; (E) BC at 3 ns of the MD; (F) superposition of the co-crystallized BC position, and the MD final position.
Figure 4
Figure 4
Molecular dynamics simulation of the B1Y:5H4I structure in water: (A) Cα RMSD; (B) Cα RMSF; (C) RMSD of B1Y relative to the protease; (D) B1Y position in the co-crystallized structure; (E) B1Y at 3 ns of the MD; (F) superposition of the co-crystallized B1Y position, and the MD final position.
Figure 5
Figure 5
Two-dimensional diagrams of the main interactions of BC and B1Y with the Zika virus protease: (A) 5YOD (md5); (B) 5YOD (em); (C) 5H4I (md5); (D) 5H4I (em).
Figure 6
Figure 6
Quantum biochemistry calculations for the PDB structures 5YOD and 5H4I modified after a 5-ns molecular dynamics simulation (top) and after classical energy minimization (bottom). (A,C) 5YOD interaction energy (black line + scatter) and the interaction energies of the individual residues included as the distance from the ligand is increased (blue scatter and blue scale right axis). (B,D) 5H4I interaction energy (black line + scatter) and the interaction energies of the individual residues included as the distance from the ligand is increased (blue scatter and blue scale right axis).
Figure 7
Figure 7
The binding site, interaction energy, and residue domain (BIRD) panels show the MFCC protein–ligand interaction energies with their respective distances to the ligand. (A,C) 5YOD (md5/dft) and 5YOD (em/dft) structures, respectively. (B,D) 5H4I (md5/dft) and 5H4I (em/dft) structures, respectively.
Figure 8
Figure 8
MM-PBSA-calculated energies for the em and md5 structures obtained from the PDB files 5H4I and 5YOD.
Figure 9
Figure 9
Energy contributions per amino acid residue for the 5YOD (md5/pbsa), 5YOD (em/pbsa), 5H4I (md5/pbsa), and 5H4I (em/pbsa) systems.
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