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Functional Loop Dynamics and Characterization of the Inactive State of the NS2B-NS3 Dengue Protease due to Allosteric Inhibitor Binding

Cite this: J. Chem. Inf. Model. 2022, 62, 16, 3800–3813
Publication Date (Web):August 11, 2022
https://doi.org/10.1021/acs.jcim.2c00461
Copyright © 2022 American Chemical Society

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    Abstract

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    Dengue virus, a flavivirus that causes dengue shock syndrome and dengue hemorrhagic fever, is currently prevalent worldwide. A two-component protease (NS2B-NS3) is essential for maturation, representing an important target for designing anti-flavivirus drugs. Previously, consideration has been centered on developing active-site inhibitors of NS2B-NS3pro. However, the flat and charged nature of its active site renders difficulties in developing inhibitors, suggesting an alternative strategy for identifying allosteric inhibitors. The allosterically sensitive site of the dengue protease is located near Ala125, between the 120s loop and 150s loop. Using atomistic molecular dynamics simulations, we have explored the protease’s conformational dynamics upon binding of an allosteric inhibitor. Furthermore, characterization of the inherent flexible loops (71–75s loop, 120s loop, and 150s loop) is carried out for allosteric-inhibitor-bound wild-type and mutant A125C variants and a comparison is performed with its unbound state to extract the structural changes describing the inactive state of the protease. Our study reveals that compared to the unliganded system, the inhibitor-bound system shows large structural changes in the 120s loop and 150s loop in contrast to the rigid 71–75s loop. The unliganded system shows a closed-state pocket in contrast to the open state for the wild-type complex that locks the protease into the open and inactive-state conformations. However, the mutant complex fluctuates between open and closed states. Also, we tried to see how mutation and binding of an allosteric inhibitor perturb the connectivity in a protein structure network (PSN) at contact levels. Altogether, our study reveals the mechanism of conformational rearrangements of loops at the molecular level, locking the protein in an inactive conformation, which may be useful for developing allosteric inhibitors.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.2c00461.

    • Average RMSD for every 200 ns of the whole protein (Table S1); average RMSD for every 200 ns of NS3 (Table S2); average RMSD for every 200 ns of NS2B (Table S3); average RMSD, radius of gyration (RoG), and solvent-accessible surface area (SASA) (Table S4); average network parameters via the NAPS server (Table S5); network component details via WebPSN (Table S6); average path summary (Table S7); per-residual decomposition of free energy for each system (Table S8); hydrogen-bond occupancy (Tabe S9); time evolution of RMSD for each system during RUN-1 and RUN-2 (Figures S1 and S2); RoG and SASA (Figure S3); potential of mean force and RMSD of the ligand (Figure S4); distribution of eigenvectors vs eigenvalues plot from PCA (Table S5); betweenness value and global meta-path from network analysis (Figure S6); per-residual decomposition of free energy (Figure S7); and protein–ligand interaction profile (Figure S8) (PDF)

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    • systems_coordinates_topology_pdb (ZIP)

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    Cited By

    This article is cited by 1 publications.

    1. Rajdip Misra, Anupam Maity, Shubham Kundu, Mrinmay Bhunia, Banadipa Nanda, Nakul C. Maiti, Uttam Pal. Loop Dynamics and Conformational Flexibility in Dengue Serine Protease Activity: Noninvasive Perturbation by Solvent Exchange. Journal of Chemical Information and Modeling 2023, 63 (7) , 2122-2132. https://doi.org/10.1021/acs.jcim.2c01349

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