CARS: A General Force Field for Carotenoids

Abstract

Carotenoids are structurally diverse isoprenoid pigments that play central roles in photosynthesis, photoprotection, membrane organization, and cellular signaling. Despite their biological and technological importance, atomistic simulations of carotenoids remain limited by the lack of a transferable force field spanning the chemical diversity of naturally occurring compounds, including glycosylated and acylated derivatives. Here we present CARS (CARotenoidS), a transferable force field for carotenoids that integrates seamlessly with the AMBER family of biomolecular force fields. Parameters were systematically optimized against 22 957 r2SCAN-3c reference energies for 25 representative molecular fragments, yielding an accurate description of polyene conformational energetics, ring rotations, and molecular geometries. Across diverse validation sets, CARS substantially outperforms GAFF2 and provides improved agreement with quantum-chemical reference data for glycosylated and acylated carotenoids. For zeaxanthin, CARS also surpasses OPLS-AA, CGenFF, and previously published carotenoid-specific parameters set in reproducing conformational energetics and structural properties. Two complementary parameter sets are provided: CARS for glycosylated and non-lipidated carotenoids, and CARS+Lipid21 for carotenoids containing saturated or monounsaturated lipid chains. By providing the first unified and transferable parameterization covering the structural diversity of natural carotenoids while remaining fully compatible with established AMBER force fields, CARS removes the need for molecule-specific reparameterization and enables reliable molecular simulations of carotenoids in proteins, membranes, and other complex biological assemblies.