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Exploring the pH- and Ligand-Dependent Flap Dynamics of Malarial Plasmepsin II

Cite this: J. Chem. Inf. Model. 2022, 62, 1, 150–158
Publication Date (Web):December 29, 2021
https://doi.org/10.1021/acs.jcim.1c01180
Copyright © 2021 American Chemical Society

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    Abstract

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    Malaria remains a global health threat─over 400,000 deaths occurred in 2019. Plasmepsins are promising targets of antimalarial therapeutics; however, no inhibitors have reached the clinic. To fuel the progress, a detailed understanding of the pH- and ligand-dependent conformational dynamics of plasmepsins is needed. Here we present the continuous constant pH molecular dynamics study of the prototypical plasmepsin II and its complexed form with a substrate analogue. The simulations revealed that the catalytic dyads D34 and D214 are highly coupled in the apo protein and that the pepstatin binding enhances the difference in proton affinity, making D34 the general base and D214 the general acid. The simulations showed that the flap adopts an open state regardless of pH; however, upon pepstatin binding the flap can close or open depending on the protonation state of D214. These and other data are discussed and compared with the off-targets human cathepsin D and renin. This study lays the groundwork for a systematic investigation of pH- and ligand-modulated dynamics of the entire family of plasmepsins to help design more potent and selective inhibitors.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.1c01180.

    • Convergence of calculated pKa values; Titration curves of the dyad; additional analysis of hydration and hydrogen bond formation of the dyad; additional analysis of the flap movement; analysis of a hydrogen bond network involving the second active site water; analysis of the hydrogen bond and electrostatic interactions involving H164, D4, or D303 (PDF)

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    Cited By

    This article is cited by 5 publications.

    1. Dulce C. Guzmán-Ocampo, Rodrigo Aguayo-Ortiz, José-Luis Velasco-Bolom, Pancham Lal Gupta, Adrian E. Roitberg, Laura Dominguez. Elucidating the Protonation State of the γ-Secretase Catalytic Dyad. ACS Chemical Neuroscience 2023, 14 (2) , 261-269. https://doi.org/10.1021/acschemneuro.2c00563
    2. Raitis Bobrovs, Emils Edgars Basens, Laura Drunka, Iveta Kanepe, Sofija Matisone, Karlis Kristofers Velins, Victor Andrianov, Gundars Leitis, Diana Zelencova-Gopejenko, Dace Rasina, Aigars Jirgensons, Kristaps Jaudzems. Exploring Aspartic Protease Inhibitor Binding to Design Selective Antimalarials. Journal of Chemical Information and Modeling 2022, 62 (13) , 3263-3273. https://doi.org/10.1021/acs.jcim.2c00422
    3. Vinicius Martins de Oliveira, Ruibin Liu, Jana Shen. Constant pH molecular dynamics simulations: Current status and recent applications. Current Opinion in Structural Biology 2022, 77 , 102498. https://doi.org/10.1016/j.sbi.2022.102498
    4. AMI TJITRARESMI, KIRKA DWI APRIALI, KAMILA NURVIANITA, IDA MUSFIROH, MOELYONO MOEKTIWARDOYO, YASMIWAR SUSILAWATI. PHARMACOKINETIC PREDICTIONS AND MOLECULAR DYNAMIC ANALYSIS OF TERPENOID AND FLAVONOID COMPOUNDS FROM MIANA LEAVES (PLECTRANTHUS SCUTELLARIOIDES (L.) R. BR.) AS AN ANTIMALARIAL CANDIDATES ON PLASMEPSIN II RECEPTOR. International Journal of Applied Pharmaceutics 2022, , 142-150. https://doi.org/10.22159/ijap.2022.v14s4.PP35
    5. Yongpeng Li, Tiantian Chen, Hang Liu, Wei Qin, Xin Yan, Kuanyu Wu-Zhang, Bowen Peng, Yaojie Zhang, Xinghao Yao, Xueqing Fu, Ling Li, Kexuan Tang. The truncated AaActin1 promoter is a candidate tool for metabolic engineering of artemisinin biosynthesis in Artemisia annua L.. Journal of Plant Physiology 2022, 274 , 153712. https://doi.org/10.1016/j.jplph.2022.153712

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