Smoother Alchemical Transformations via Enveloping Distribution Sampling for Free-Energy Estimation

Area of Science:

• Computational Chemistry
• Statistical Mechanics
• Biophysics

Background:

• Accurate relative free energy calculations are crucial for molecular modeling.
• Current methods like energy interpolation (EI) can suffer from insufficient phase-space overlap.
• This limits accuracy in equilibrium (EQ) and nonequilibrium (NEQ) simulations.

Purpose of the Study:

• To introduce and validate the enveloping distribution sampling (EDS) coupling scheme.
• To demonstrate EDS as a more flexible and accurate alternative to EI.
• To improve the smoothness of alchemical transformations in free energy calculations.

Main Methods:

• Generalized energy interpolation using linear combination of Boltzmann factors.
• Introduction of a negative smoothing parameter in EDS to enhance phase-space curvature.
• Validation across model systems (harmonic oscillators, Ising models) and absolute hydration free-energy (AHFE) calculations.

Main Results:

• EDS demonstrated superior accuracy and statistical robustness compared to EI in model systems.
• EDS significantly improved AHFE calculations in the NEQ regime.
• The negative smoothing parameter in EDS effectively avoided phase transitions, ensuring smoother transformations.

Conclusions:

• The EDS scheme offers a more flexible and effective approach for free energy calculations.
• EDS enhances simulation accuracy and reliability, particularly in NEQ scenarios.
• This method holds promise for advancing computational predictions in solvation and binding energies.