Computational Investigation of Chiral DOTA-Derivatives: Insights into Structure, Stability, and Relaxivity

DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid) is a widely studied macrocyclic ligand for Gd³⁺ chelation, particularly in the context of magnetic resonance imaging (MRI). In this study, classical and ab initio molecular dynamics simulations were performed to investigate the coordination behavior and stability of [Ln(DOTA)]^-, [Ln(HMDOTA-SS)]^-, and [Ln(T)]^- (Ln³⁺= La³⁺, Gd³⁺, and Lu³⁺) complexes in an aqueous solution at various temperatures (25, 45, and 65 °C). The simulations reveal temperature-dependent shifts between SAP and TSAP isomers with enhanced stability correlated to reduced structural fluctuations. Lanthanide contraction was evident from the leftward shifts in the radial distribution functions. Binding energies follow the trend [Ln(T)]^-> [Ln(HMDOTA-SS)]^- > [Ln(DOTA)]^-, with [Ln(T)]^- and [Ln(HMDOTA-SS)]^- showing greater thermodynamic stability than [Ln(DOTA)]^-. The rigid hydrophilic groups in HMDOTA-SS and the T ligand accelerate the water exchange rate (<i>k</i>_ex²⁹⁸) via increased steric hindrance and altered rotational correlation time. Further, the zero-field splitting (ZFS), which influences the electronic relaxation, is modulated via magnetostructural correlation. The increased Gd-O(w) bond length raises the axial ZFS (D), especially upon loss of coordinated water. These insights support the design of more stable, high-relaxivity MRI contrast agents.