Single-Parameter Scaling Strategy for Force Field Optimization: A Case Study on Alkane Melting-Point Prediction

Classical force fields critically determine the reliability of molecular simulations, yet simultaneous optimization of their high-dimensional parameters remains inefficient and risks disrupting cross-system compatibility. Using alkane melting points as the target property, this work systematically investigates how scaling individual parameters in multiscale force fields affects prediction accuracy. Three linear alkanes (octane (C₈), hexadecane (C₁₆), and tetracosane (C₂₄)) were evaluated with two all-atom (AA) models (L-OPLS, CHARMM36), three united-atom (UA) models (TraPPE-UA, PYS, and OPLS-UA), and one coarse-grained (CG) model (Martini 3). Unmodified force field tests showed that L-OPLS, CHARMM36, PYS, and TraPPE-UA predicted melting points within 7% of experimental values, whereas OPLS-UA consistently overpredicted all alkane melting points, and Martini 3 exhibited significant overprediction for C₈. Parameter scaling revealed that, for the UA models, bond force constant (k_b) and angle force constant (k_a) negligibly impact melting points, whereas melting points positively correlate with dihedral force constant (k_n) and Lennard-Jones (LJ) parameters (ε, σ). Since LJ parameter scaling substantially perturbs liquid densities and self-diffusion coefficients─unlike dihedral adjustments─scaling k_n emerges as the optimal strategy. Melting points were corrected to experimental values with ± 10% k_n scaling for TraPPE-UA and PYS, whereas OPLS-UA required ≈50% reduction of k_n. For AA models, partial charge scaling effectively tuned melting points with minimal effects on the liquid properties. In Martini 3, angle force constant scaling improved predictions (except for angle-lacking C₈). This systematic single-parameter scaling (SPS) delineates structure-property relationships between force field parameters and alkane thermophysical behavior, providing an efficient strategy for the rapid refinement of established force fields.