LignAmb25: A Comprehensive AMBER Force Field Addressing Lignin's Structural and Chemical Diversity

LignAmb25 is a comprehensive force field for lignin molecular dynamics simulations implemented natively within the AMBER package. The force field includes parameters for all common monolignol units (p-coumaryl, coniferyl, caffeyl, and sinapyl alcohol) and their associated linkages ({beta}-O4, {beta}-5, {beta}-{beta}, {beta}-1, 5-5, 5-O4, -O4, BDO, and DBDO), along with less commonly encountered units such as tricin, spirodienones, and hydroxystilbenes. This enables simulations of both softwood and hardwood lignin structures with compositions that would be difficult to isolate experimentally. Force field parameters were initially derived from the GAFF2 force field and systematically optimized using quantum mechanical calculations at the {omega}B97X-D4/def2-TZVPP level of theory on conformer ensembles derived via the CREST/CENSO conformational sampling toolchain. Partial atomic charges were derived using the RESP methodology, consistent with AMBER conventions. Experimentally measured crystal structures of lignin simulated with LignAmb25 accurately retain their packing based on calculations of the RMSD and density error compared to the deposited crystal structure, thereby exceeding the performance of the lignin force field for CHARMM. Additionally, LignAmb25 is shown to reliably estimate the enthalpy of vaporization and the absolute hydration free energy of lignin-related compounds. The LignAmb25 force field is provided in two variants: LignAmb25Solo, a standalone version not meant for use with other biomolecular force fields that focuses on accurate modelling of lignin-solvent interactions, and LignAmb25HF, a version that is compatible with all other major biomolecular force fields in the AMBER molecular dynamics suite. This includes force fields of the GLYCAM (carbohydrates), ff19SB (proteins), and LIPID (lipids) families, as well as the DNA and RNA force fields routinely used in AMBER. The LignAmb25 force field will be distributed as of AMBER 26. Statement of significanceLignin, a complex aromatic heteropolymer comprising up to 40% of plant biomass, remains one of the most challenging biopolymers to characterize experimentally due to its structural heterogeneity, recalcitrance against depolymerization and selective chemical conversion, and lack of a defined primary sequence. Traditional wet-lab analytical methods face significant limitations, including lignins poor solubility, tendency to aggregate, and structural modifications during extraction and analysis. These experimental challenges make computational approaches essential for understanding the molecular basis of lignins physicochemical properties and for advancing lignocellulosic biomaterial applications. We present LignAmb25, a molecular mechanics force field for lignin implemented within AMBER, enabling researchers to investigate lignin structures and dynamics under conditions difficult to access experimentally. LignAmb25 integrates into the AMBER force field system and represents an alternative to the lignin force field for CHARMM. It improves upon the latter by including spirodienones and hydroxystilbenes as less commonly encountered monolignol units and the addition of several new linkages.