BPS2026 – Singularity-free force fields for free-energy perturbation: A new framework for robust alchemical simulations

Alchemical free-energy calculations are essential for drug discovery and biomolecular thermodynamics, yet classical force fields create significant challenges due to mathematical singularities in Lennard-Jones and Coulombic potentials. These singularities necessitate complex softcore modifications that can distort energy landscapes and complicate convergence. We introduce DEGAUSS, a force field framework that intrinsically eliminates singularities by replacing Lennard-Jones potentials with double exponential functions and point charges with Gaussian charge distributions, enabling robust free-energy perturbation without auxiliary softcore potentials. Comprehensive validation demonstrates that DEGAUSS accurately reproduces classical force field behavior. Water models (TIP3P and OPC3) show quantitative agreement in thermodynamic properties across 240-380 K. Biomolecular systems including alanine dipeptide and proteins (1ENH, 1UBQ, and 1PGA) maintain correct conformational preferences and structural stability. Critically, alchemical calculations of NaCl solvation demonstrate singularity-free particle annihilation throughout the transformation pathway while preserving thermodynamic accuracy. DEGAUSS represents a paradigm shift for alchemical simulations, offering a mathematically robust framework that eliminates the singularity problem inherent to classical potentials. This approach promises improved reliability for binding free-energy calculations and simplified protocols for drug discovery applications.