Molecular Insights into the Temperature-Dependent Binding and Conformational Dynamics of Noraucuparin with Bovine Serum Albumin: A Microsecond-Scale MD Simulation Study

Background/Objectives: Understanding the molecular interactions between small bioactive compounds and serum albumins is essential for drug development and pharmacokinetics. Noraucuparin, a biphenyl-type phytoalexin with promising pharmacological properties, has shown a strong binding affinity to bovine serum albumin (BSA), a model protein for drug transport. This study aims to elucidate the structural and energetic characteristics of the noraucuparin–BSA complex under physiological and slightly elevated temperatures. Methods: Microsecond-scale molecular dynamics (MD) simulations and Molecular Mechanics Generalized Born Surface Area (MMGBSA)-binding-free energy calculations were performed to investigate the interaction between noraucuparin and BSA at 298 K and 310 K. Conformational flexibility and per-residue energy decomposition analyses were conducted, along with interaction network mapping to assess ligand-induced rearrangements. Results: Noraucuparin preferentially binds to site II of BSA, near the ibuprofen-binding pocket, with stabilization driven by hydrogen bonding and hydrophobic interactions. Binding at 298 K notably increased the structural mobility of BSA, affecting its global conformational dynamics. Key residues, such as Trp213, Arg217, and Leu237, contributed significantly to complex stability, and the ligand induced localized rearrangements in the protein’s intramolecular interaction network. Conclusions: These findings offer insights into the dynamic behavior of the noraucuparin–BSA complex and enhance the understanding of serum albumin–ligand interactions, with potential implications for drug delivery systems.