Efficient Alchemical Intermediate States in Free Energy Calculations Using λ-Enveloping Distribution Sampling

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Biophysics

Background:

• Alchemical free energy calculations require intermediate states (λ) for convergence.
• Optimizing these intermediate states is crucial for efficient molecular simulations.
• Conventional methods can be computationally intensive and require careful parameterization.

Purpose of the Study:

• To develop an automated procedure for selecting optimal parameters for the λ-EDS method.
• To improve the efficiency and accuracy of alchemical free energy calculations.
• To demonstrate the utility of the automated λ-EDS parameter selection across various systems.

Main Methods:

• Implementation of an automated parameter selection algorithm for λ-EDS.
• Utilizing λ-EDS, which combines minimum variance pathway and EDS properties.
• Testing the method on simple systems (harmonic oscillators, dihedral angles, charge creation in water) and 12 organic molecules.

Main Results:

• The developed automated procedure effectively selects λ-EDS parameters for optimal performance.
• λ-EDS allows for larger steps along the alchemical pathway compared to conventional methods.
• Accurate absolute hydration free energies were calculated for 12 small organic molecules.

Conclusions:

• The automated parameter selection for λ-EDS significantly enhances sampling efficiency in free energy calculations.
• This method eliminates the need for soft-core potentials, simplifying calculations.
• The approach is validated for diverse chemical systems, including hydration free energy calculations.