Toward an Enhanced Sampling Molecular Dynamics Method for Studying Ligand-Induced Conformational Changes in Proteins

Area of Science:

• Computational Biology
• Biophysics
• Molecular Dynamics

Background:

• Enhanced sampling molecular dynamics methods often require user-defined collective variables and known start/end structures.
• Accurately simulating large conformational changes in proteins, especially ligand-induced ones, remains computationally challenging.

Purpose of the Study:

• To develop a novel molecular dynamics framework for studying ligand-induced protein conformational changes.
• To overcome limitations of existing enhanced sampling methods, such as the need for collective variables and predefined endpoints.

Main Methods:

• A new molecular dynamics method utilizing biasing forces derived from nonbonded protein-ligand interactions.
• The method requires only a single input structure and does not rely on collective variables.
• Proof-of-concept simulations performed on small molecules and two proteins (ribose-binding and glutamine-binding proteins).

Main Results:

• Accelerated conformational changes observed in test molecules.
• Achieved high accuracy (0.75 Å RMSD) for ribose-binding protein domain closure within 50 ns, a feat not seen in unbiased simulations.
• Observed a skewed closed structure for glutamine-binding protein, suggesting potential suppression of protein-protein interactions by specific ligand interactions.

Conclusions:

• The proposed molecular dynamics framework effectively simulates ligand-induced conformational changes.
• This method offers a more accessible and efficient approach compared to traditional enhanced sampling techniques.
• Findings highlight the role of specific protein-ligand interactions in modulating protein dynamics.