Zooming across the Alchemical Space

Area of Science:

• Computational chemistry and biophysics
• Molecular modeling and simulation

Background:

• Alchemical transformations are crucial for molecular simulations and free-energy calculations.
• Discretization of the alchemical parameter (λ) impacts simulation reliability and efficiency.
• Standard methods like Free-Energy Perturbation (FEP) and Thermodynamic Integration (TI) struggle with large molecular transformations due to extensive sampling requirements.

Purpose of the Study:

• To introduce a novel enhanced-sampling method, WTM-λABF, for efficient alchemical transformations.
• To address the computational limitations of traditional methods for complex molecular changes.
• To accelerate free-energy calculations in molecular simulations.

Main Methods:

• Combining λ-dynamics (treating λ as a dynamic variable) with well-tempered metadynamics-extended adaptive biasing force (WTM-eABF).
• Treating λ as a continuously varying collective variable (CV) with a bin-discretized bias.
• Applying the WTM-λABF method to calculate free energies of hydration, protein-ligand binding, and amino-acid mutations.

Main Results:

• WTM-λABF demonstrates faster convergence compared to standard FEP and λ-ABF, especially with an increasing number of intermediates.
• The method efficiently handles alchemical transformations with up to 1,000 intermediates.
• WTM-λABF accurately tackles transformations involving large moieties and significant potential-energy changes.
• Rapid exploration of continuous λ-space accelerates sampling in orthogonal spaces.

Conclusions:

• WTM-λABF offers a significant advancement for alchemical free-energy calculations.
• The method enhances computational feasibility and accuracy for complex molecular transformations.
• WTM-λABF has the potential to become a foundational tool for drug discovery, protein engineering, and biophysical applications.