Multiple Molecule λ-Dynamics: Probing Drug Resistance with Concurrent Protein and Ligand Perturbations

Area of Science:

• Computational chemistry
• Molecular dynamics
• Drug discovery

Background:

• Alchemical free energy calculations are common in drug discovery.
• Drug resistance due to missense mutations is a challenge.
• Traditional methods struggle to evaluate multiple molecular modifications efficiently.

Purpose of the Study:

• To introduce and validate Multiple Molecule λ-Dynamics (MMλD) for drug resistance studies.
• To assess MMλD's ability to simulate simultaneous ligand and protein perturbations.
• To explore drug resistance in Abl kinases using MMλD.

Main Methods:

• Developed and applied Multiple Molecule λ-Dynamics (MMλD).
• Performed simultaneous ligand and protein perturbations in a single simulation.
• Sampled ligands bound to native and T315I mutant Abl kinases.

Main Results:

• MMλD showed high agreement with conventional λ-dynamics (λD) calculations (0.21 kcal/mol error).
• MMλD results closely matched experimental data (0.94 kcal/mol error).
• Identified protein sequence-specific ligand conformational sampling.

Conclusions:

• MMλD is a powerful and accurate tool for drug discovery, particularly for addressing drug resistance.
• The method facilitates the evaluation of multiple molecular modifications in a single simulation.
• MMλD advances the study of drug resistance mechanisms in targeted therapies.