ArticleBiophysical journal2021
Membrane-Mediated Ligand Unbinding of the PK-11195 Ligand from TSPO.
Article in Biophysical journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Ligand-Binding Free Energy Simulations of Membrane Proteins.Advances in experimental medicine and biology · 2026Review
- Investigating the unbinding mechanisms and kinetics of MmpL3 inhibitors: A computational study.Protein science : a publication of the Protein Society · 2025Article
- Current advances in the structure-activity relationship (SAR) analysis of the old/new 18-kDa translocator protein ligands.Molecular diversity · 2025Review
- Markov State Models with Weighted Ensemble Simulation: How to Eliminate the Trajectory Merging Bias.Journal of chemical theory and computation · 2025Article
- SIFD-associated TRNT1 deficiency unveils importance of TSPO during macrophage antibacterial and antiviral responses.Frontiers in immunology · 2025Article
- Gating residues govern ligand unbinding kinetics from the buried cavity in HIF-2α PAS-B.Protein science : a publication of the Protein Society · 2024Article
- Revisiting Textbook Azide-Clock Reactions: A "Propeller-Crawling" Mechanism Explains Differences in Rates.Journal of the American Chemical Society · 2024Article
- Targeting the Translocator Protein (18 kDa) in Cardiac Diseases: State of the Art and Future Opportunities.Journal of medicinal chemistry · 2024Review
- New TSPO Crystal Structures of Mutant and Heme-Bound Forms with Altered Flexibility, Ligand Binding, and Porphyrin Degradation Activity.Biochemistry · 2023Article
- Quality over quantity: Sampling high probability rare events with the weighted ensemble algorithm.Journal of computational chemistry · 2023Article
- Binding Kinetics Toolkit for Analyzing Transient Molecular Conformations and Computing Free Energy Landscapes.The journal of physical chemistry. A · 2022Article
- Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry.Nature communications · 2022Article
- The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing.ACS omega · 2022Review
- Mechanistic Insights into Passive Membrane Permeability of Drug-like Molecules from a Weighted Ensemble of Trajectories.Journal of chemical information and modeling · 2022Article
- Enhanced-Sampling Simulations for the Estimation of Ligand Binding Kinetics: Current Status and Perspective.Frontiers in molecular biosciences · 2022Review
- From Data to Knowledge: Systematic Review of Tools for Automatic Analysis of Molecular Dynamics Output.Frontiers in pharmacology · 2022Review
- The Next Frontier for Designing Switchable Proteins: Rational Enhancement of Kinetics.The journal of physical chemistry. B · 2021Article
- The RED scheme: Rate-constant estimation from pre-steady state weighted ensemble simulations.The Journal of chemical physics · 2021Article
- The Interplay of Cholesterol and Ligand Binding inMolecules (Basel, Switzerland) · 2021Article
- Wepy: A Flexible Software Framework for Simulating Rare Events with Weighted Ensemble Resampling.ACS omega · 2020Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is of longstanding medical interest as both a biomarker for neuroinjury and a potential drug target for neuroinflammation and other disorders. Recently, it was shown that ligand residence time is a key factor determining steroidogenic efficacy of TSPO-binding compounds. This spurs interest in simulations of (un)binding pathways of TSPO ligands, which could reveal the molecular interactions governing ligand residence time. In this study, we use a weighted ensemble algorithm to determine the unbinding pathway for different poses of PK-11195, a TSPO ligand used in neuroimaging. In contrast with previous studies, our results show that PK-11195 does not dissociate directly into the solvent but instead dissociates via the lipid membrane by going between the transmembrane helices. We analyze this path ensemble in detail, constructing descriptors that can facilitate a general understanding of membrane-mediated ligand binding. We construct a set of Markov state models augmented with additional straightforward simulations to determine pose-specific ligand residence times. Together, we combine over 40 μs of trajectory data to form a coherent picture of the ligand binding landscape. We find that multiple starting poses yield residence times that roughly agree with the experimental quantity. The ligand binding transition states predicted by these Markov state models occur when PK-11195 is already in the membrane and involves only minimal ligand-protein interactions. This has implications for the design of new long-residence-time TSPO ligands.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.