Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov...

Area of Science:

• Structural biology
• Biophysics
• Computational chemistry

Background:

• Protein structure and dynamics are crucial for function.
• Ligand binding is central to drug discovery and biological processes.
• Understanding protein-ligand interactions requires insights into dynamic conformational changes.

Purpose of the Study:

• To investigate the relationship between conformational flexibility and ligand-binding kinetics.
• To explore the conformational landscape of the serine protease Trypsin.
• To analyze how different protein conformations affect binding affinity and rates with Benzamidine.

Main Methods:

• Extensive molecular dynamics (MD) simulations (150 microseconds).
• Analysis using Markov state modeling (MSM).
• Investigated Trypsin-Benzamidine interactions.

Main Results:

• Identified seven metastable conformations of Trypsin with distinct binding pocket structures.
• These conformations interconvert on the tens-of-microseconds timescale.
• Conformations exhibited varied substrate-binding affinities and kinetic rates for Benzamidine.

Conclusions:

• Protein conformational plasticity is evident in Trypsin.
• Identified conformations are relevant to existing Protein Data Bank structures of mutants and related proteases.
• Conformational states can be stabilized by ligands or sequence modifications, impacting binding.