Protein-Ligand Dissociation Simulated by Parallel Cascade Selection Molecular Dynamics.

Area of Science:

• Biochemistry
• Computational Chemistry
• Molecular Dynamics

Background:

• Understanding ligand-protein dissociation is crucial for drug discovery.
• Conventional molecular dynamics (MD) simulations often struggle to capture rare dissociation events.
• Hen egg white lysozyme and tri-N-acetyl-d-glucosamine serve as a model system for studying carbohydrate-protein interactions.

Purpose of the Study:

• To investigate the dissociation mechanism of tri-N-acetyl-d-glucosamine from hen egg white lysozyme.
• To evaluate the efficiency of parallel cascade selection molecular dynamics (PaCS-MD) in accelerating rare events.
• To accurately calculate the binding free energy using advanced computational methods.

Main Methods:

• Parallel cascade selection molecular dynamics (PaCS-MD) involving cycles of unbiased MD simulations.
• Selection and rerandomization of initial velocities to enhance rare event probability.
• Markov state model (MSM) analysis of PaCS-MD trajectories for free energy calculations.
• Comparison with umbrella sampling (US) and steered MD (SMD) methods.

Main Results:

• PaCS-MD significantly accelerated the dissociation process, achieving it within 10-100 ns compared to conventional MD.
• Velocity rerandomization was key for dissociation from the bound state, while diffusion dominated the unbound state.
• PaCS-MD combined with MSM provided binding free energy results closest to experimental values.
• PaCS-MD/MSM demonstrated robustness against simulation parameter variations and yielded low standard errors.

Conclusions:

• PaCS-MD is a highly effective method for studying ligand-protein dissociation and rare events.
• The combination of PaCS-MD and MSM offers a reliable approach for accurate binding free energy calculations.
• This study provides valuable insights into the dissociation dynamics of carbohydrate-protein complexes.