Mechanistic insights into the binding of six ligands to phenylalanine aminomutase from Fusarium oxysporum: a molecular docking and dynamics simulation study

Paclitaxel, a diterpenoid anticancer agent, is biosynthesized through a complex enzymatic pathway in which phenylalanine aminomutase (PAM) plays a central catalytic role. Despite its biosynthetic importance, the molecular determinants underlying PAM–ligand interactions in fungal systems remain poorly understood. In the present study, an integrated computational framework combining molecular docking with 500 nsec molecular dynamics (MD) simulations was employed to systematically characterize the binding affinity, conformational stability, and dynamic behavior of six structurally diverse ligands—α-phenylalanine, salicylic acid, benzoic acid, arachidonic acid, cinnamic acid, and chitosan—in complex with the PAM enzyme from Fusarium oxysporum . Cinnamic acid exhibited the highest overall binding affinity (ΔG_Bind = − 35.65 ± 3.46 kcal mol⁻¹), followed by α-phenylalanine (− 33.96 ± 3.30 kcal mol⁻¹), with van der Waals interactions serving as the dominant stabilizing force across all high-affinity complexes. Salicylic acid emerged as a potent conformational stabilizer, maintaining ligand RMSD below 1.0 Å and the lowest Radius of gyration (Rg)(32.38 ± 0.03 Å). Interaction fingerprint analysis revealed persistent hydrogen-bond contacts at residues THR_181, ILE_182, SER_183, and ALA_184 for salicylic acid and cinnamic acid, whereas benzoic acid, arachidonic acid, and chitosan exhibited transient, non-specific interactions inconsistent with productive binding. Free energy landscape (FEL) analysis revealed that high-affinity ligands restricted the conformational space sampled by PAM, resulting in a single, well-defined low-energy basin. These findings provide mechanistic insight into PAM–ligand recognition and offer a structural basis for the rational modulation of fungal taxane biosynthesis.