Quantum-Accurate Conformational Stabilities and Vibrational Dynamics in Molecules and Proteins with Machine-Learned Force Fields

Abstract

Biomolecular thermodynamics and spectroscopy depend on relative conformer energies, local curvatures, and collective dipole fluctuations on the potential-energy surface. Conventional molecular mechanics force fields enable large-scale simulations, but their fixed functional forms can misrepresent infrared intensities, mode character, and environment-dependent vibrational response. Here we assess general-purpose machine-learned force fields across small molecules, finite-temperature infrared spectra, gas-phase peptides, and monomeric, oligomeric, and solvated protein assemblies. To enable this analysis, we introduce QVib, a dataset of 293 molecules and 1365 conformers, together with peptide amide-band benchmarks and p53 oligomerization-domain models, to evaluate vibrational transferability from DFT references to experimental spectra. Across these systems, machine-learned force fields substantially improve over molecular mechanics in reproducing DFT-level forces, vibrational frequencies, densities of states, mode eigenvectors, conformational energetics, and experimental infrared spectra. Among models with explicit long-range electrostatics, SO3LR provides the most favourable accuracy-cost balance for the biomolecular systems considered. These results show that machine-learned force-field dynamics can recover collective, environment-dependent vibrational landscapes at near-DFT fidelity, enabling spectroscopically validated biomolecular simulations at force-field-like cost.