Efficient construction of a diverse conformational library for amyloid-β as an intrinsically disordered protein

Salehi, Najmeh; Amininasab, Mehriar; Firouzi, Rohoullah; Karimi‐Jafari, Mohammad Hossein

doi:10.1016/j.jmgm.2019.01.009

Cited by 9 publications

(19 citation statements)

References 65 publications

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“…For this purpose, a computational pipeline in the framework of the ensemble docking strategy has been proposed in which a structurally heterogeneous ensemble of conformations of A β 42 is used. The ensemble is generated by the Blockwise Excursion Sampling (BES) protocol 70 in which the conformational sampling is performed on the basis of many uncorrelated short-time MD simulations starting from different reasonable points of the accessible phase space.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, 2,000 excursion chains were performed such that all excursion chains were started from a fully extended structure; excursion chain refers to a sequence of MD and SA blocks in the BES protocol, for details and terminology please see Ref. 70 .…”

Section: Protein and Ligand Library Preparationmentioning

confidence: 99%

“…The strategy of choosing the initial conditions controls the effectiveness of this approach and its ability to enhance conformational sampling performance. [66][67][68][69][70] We have recently proposed a new efficient algorithm for comprehensive exploring of the conformational space of IDPs, called Blockwise Excursion Sampling (BES). 39 It uses simulated annealing (SA) to find different low energy states of various regions of conformational space as optimal starting configurations for short conventional MD simulations.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that the protocol is successful in generating a diverse conformational library for IDP conformations in agreement with experimental data. 70…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that the protocol is successful in generating a diverse conformational library for IDP conformations in agreement with experimental data. 70 In this work, we applied the BES protocol to generate a reliable structural library for the full-length human Amyloid-β (Aβ42) monomer involved in Alzheimer's disease. 2,5,[11][12]27,35,37,39 Through ensemble docking approach, catechins, that are important natural polyphenolic compounds, were docked onto the surfaces to identify the binding "hot spots" on the Aβ42 monomers.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Catechins Binding Pockets in Monomeric Aβ₄₂Through Ensemble Docking and MD Simulations

Gracia

Firouzi

Sowlati‐Hashjin

et al. 2022

Preprint

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The assembly of the Amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer's disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aβ, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline - in the framework of the ensemble docking strategy - to identify catechins' binding pockets in monomeric Aβ42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ42. Also, it has been found that all the studied ligands, especially the EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of the Aβ. Our findings are evaluated and confirmed with multi-microsecond MD simulations. Finally, it is suggested that our proposed pipeline, with low computational cost in comparison with MD simulations, is a suitable approach for the virtual screening of ligand libraries against Aβ.

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Section: Discussionmentioning

confidence: 99%

Section: Protein and Ligand Library Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…It has been shown that the protocol is successful in generating a diverse conformational library for IDP conformations in agreement with experimental data. 70…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Identification of Catechins Binding Pockets in Monomeric Aβ₄₂Through Ensemble Docking and MD Simulations

Gracia

Firouzi

Sowlati‐Hashjin

et al. 2022

Preprint

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Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

2022

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An attractive drug target to combat COVID‐19 is the main protease (Mpro) because of its key role in the viral life cycle by processing the polyproteins translated from the viral RNA. Studying the crystal structures of the protease is important to enhance our understanding of its mechanism of action at the atomic‐level resolution, and consequently may provide crucial structural insights for structure‐based drug discovery. In the current study, we report a comparative structural analysis of the Mpro substrate binding site for both apo and holo forms to identify key interacting residues and conserved water molecules during the ligand‐binding process. It is shown that in addition to the catalytic dyad residues (His41 and Cys145), the oxyanion hole residues (Asn142–Ser144) and residues His164–Glu166 form essential parts of the substrate‐binding pocket of the protease in the binding process. Furthermore, we address the issue of the substrate‐binding pocket flexibility and show that two adjacent loops in the Mpro structures (residues Thr45–Met49 and Arg188–Ala191) with high flexibility can regulate the binding cavity’ accessibility for different ligand sizes. Moreover, we discuss in detail the various structural and functional roles of several important conserved and mobile water molecules within and around the binding site in the proper enzymatic function of Mpro. We also present a new docking protocol in the framework of the ensemble docking strategy. The performance of the docking protocol has been evaluated in predicting ligand binding pose and affinity ranking for two popular docking programs; AutoDock4 and AutoDock Vina. Our docking results suggest that the top‐ranked poses of the most populated clusters obtained by AutoDock Vina are the most important representative docking runs that show a very good performance in estimating experimental binding poses and affinity ranking.

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Thermal stability enhancement: Fundamental concepts of protein engineering strategies to manipulate the flexible structure

Rahban

Zolghadri

Salehi

et al. 2022

International Journal of Biological Macromolecules

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Efficient construction of a diverse conformational library for amyloid-β as an intrinsically disordered protein

Cited by 9 publications

References 65 publications

Identification of Catechins Binding Pockets in Monomeric Aβ₄₂Through Ensemble Docking and MD Simulations

Identification of Catechins Binding Pockets in Monomeric Aβ₄₂Through Ensemble Docking and MD Simulations

Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

Thermal stability enhancement: Fundamental concepts of protein engineering strategies to manipulate the flexible structure

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Efficient construction of a diverse conformational library for amyloid-β as an intrinsically disordered protein

Cited by 9 publications

References 65 publications

Identification of Catechins Binding Pockets in Monomeric Aβ42Through Ensemble Docking and MD Simulations

Identification of Catechins Binding Pockets in Monomeric Aβ42Through Ensemble Docking and MD Simulations

Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

Thermal stability enhancement: Fundamental concepts of protein engineering strategies to manipulate the flexible structure

Contact Info

Product

Resources

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Identification of Catechins Binding Pockets in Monomeric Aβ₄₂Through Ensemble Docking and MD Simulations

Identification of Catechins Binding Pockets in Monomeric Aβ₄₂Through Ensemble Docking and MD Simulations