Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics

Area of Science:

• Computational chemistry
• Molecular dynamics
• Biophysics

Background:

• Flexible ligands exhibit multiple binding conformations due to internal bond rotations.
• Understanding these binding modes is crucial for elucidating stabilizing interactions and accurately predicting binding affinities.

Purpose of the Study:

• To develop and validate a hybrid molecular dynamics (MD)/nonequilibrium candidate Monte Carlo (NCMC) method.
• To efficiently sample diverse binding modes of flexible ligands and estimate their population distributions.
• To reduce the computational cost associated with analyzing ligand binding conformations.

Main Methods:

• A hybrid MD/NCMC approach was employed, integrating classical MD simulations with NCMC move proposals.
• NCMC move proposals involved alchemically turning ligand interactions off and on, with intermediate rotation around rotatable bonds.
• Alchemical transformations facilitated protein and water relaxation, enhancing move acceptance rates.

Main Results:

• The MD/NCMC method successfully reproduced distinct binding modes for inhibitors targeting c-Jun N-terminal kinase-1 and cyclin-dependent kinase 2.
• The computational cost was significantly lower compared to conventional MD and umbrella sampling techniques.
• The method accurately estimated the population distribution of different binding modes.

Conclusions:

• The hybrid MD/NCMC method provides an efficient and accurate means to study flexible ligand binding modes.
• This computational approach offers a valuable tool for drug discovery and understanding ligand-protein interactions.
• The developed method is accessible through the BLUES software package.