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Determination of Protein-ligand Interactions Using Differential Scanning Fluorimetry
Published on: September 13, 2014
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Temperature Accelerated Sliced Sampling to Probe Ligand Dissociation from Protein
Shubhandra Tripathi1, Nisanth N Nair1
1Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India.
Journal of Chemical Information and Modeling
|August 4, 2023
Summary
Temperature accelerated sliced sampling (TASS) overcomes challenges in modeling protein-ligand unbinding by efficiently exploring conformational states. This method successfully determined avibactam unbinding energetics and pathways from Class C β-lactamase.
Area of Science:
- Computational Chemistry
- Biophysics
- Molecular Dynamics
Background:
- Modeling protein-ligand unbinding is crucial for drug discovery but faces challenges due to entropic bottlenecks and slow conformational sampling.
- Conventional enhanced sampling methods require extensive simulation times to overcome free energy barriers and local minima.
Purpose of the Study:
- To demonstrate the efficacy of Temperature Accelerated Sliced Sampling (TASS) for studying ligand unbinding mechanisms.
- To apply TASS to investigate the unbinding of avibactam from Class C β-lactamase (CBL).
Main Methods:
- Utilized Temperature Accelerated Sliced Sampling (TASS) to enhance conformational sampling during ligand unbinding simulations.
- Applied TASS to simulate the unbinding of avibactam inhibitor molecules from the CBL active site.
Main Results:
- Successfully extracted free energy landscapes and unbinding pathways for CBL-avibactam.
- Identified critical molecular interactions governing the unbinding process using TASS simulations.
Conclusions:
- TASS is an effective approach to overcome sampling limitations in ligand unbinding studies.
- The TASS methodology provides valuable insights into inhibitor-protein interactions and unbinding mechanisms.
