ArticleScientific reports2021
Cryptic-site binding mechanism of medium-sized Bcl-xL inhibiting compounds elucidated by McMD-based dynamic docking simulations.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 22 citations in OpenAlex.
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- Molecular recognition of natural compounds by MR1 and their implication in MAIT cell activation elucidated through McMD-based dynamic docking simulations.Scientific reports · 2025Article
- Familial Episodic Pain Syndrome: A Japanese Family Harboring the Novel Variant c.2431C>T (p.Leu811Phe) in SCN11A.Biochemical genetics · 2025Article
- A virtual system-coupled molecular dynamics simulation free from experimental knowledge on binding sites: Application to RNA-ligand binding free-energy landscape.Biophysics and physicobiology · 2025Article
- Binding Mechanism of Riboswitch to Natural Ligand Elucidated by McMD-Based Dynamic Docking Simulations.ACS omega · 2024Article
- A practical guide to machine-learning scoring for structure-based virtual screening.Nature protocols · 2023Review
- Elucidation of binding mechanism, affinity, and complex structure between mWT1 tumor-associated antigen peptide and HLA-A*24:02.Protein science : a publication of the Protein Society · 2023Article
- Mutual induced-fit mechanism drives binding between intrinsically disordered Bim and cryptic binding site of Bcl-xL.Communications biology · 2023Article
- Advancing the field of computational drug design using multicanonical molecular dynamics-based dynamic docking.Biophysical reviews · 2022Review
- Enhanced sampling without borders: on global biasing functions and how to reweight them.Physical chemistry chemical physics : PCCP · 2022Review
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We have performed multicanonical molecular dynamics (McMD) based dynamic docking simulations to study and compare the binding mechanism between two medium-sized inhibitors (ABT-737 and WEHI-539) that bind to the cryptic site of Bcl-xL, by exhaustively sampling the conformational and configurational space. Cryptic sites are binding pockets that are transiently formed in the apo state or are induced upon ligand binding. Bcl-xL, a pro-survival protein involved in cancer progression, is known to have a cryptic site, whereby the shape of the pocket depends on which ligand is bound to it. Starting from the apo-structure, we have performed two independent McMD-based dynamic docking simulations for each ligand, and were able to obtain near-native complex structures in both cases. In addition, we have also studied their interactions along their respective binding pathways by using path sampling simulations, which showed that the ligands form stable binding configurations via predominantly hydrophobic interactions. Although the protein started from the apo state, both ligands modulated the pocket in different ways, shifting the conformational preference of the sub-pockets of Bcl-xL. We demonstrate that McMD-based dynamic docking is a powerful tool that can be effectively used to study binding mechanisms involving a cryptic site, where ligand binding requires a large conformational change in the protein to occur.
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