Lanthanide (Ln) complex of polymethylated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand bearing four ring SSSS methyl groups and four SSSS methyl substituents in the acetate arms (SSSS-SSSS-M4DOTMA) forms a highly rigid and symmetrical complex in solution, which can then assist in the elucidation of protein structures in solution. Modification of one of the pendant arms with a pyridyl disulfide group (Ln-SSSS-SSSS-M8SPy) allows conjugation with the free cysteines of a protein. However, the presence of conformational isomers that produce additional resonances can significantly complicate the structural analyses in solution. Determination of the relative isomer populations can aid in the proper selection of lanthanide tags for protein structural studies. The isomeric populations in solution were carefully investigated by RP-HPLC and mass spectrometry, and were confirmed by extensive NMR studies. It was revealed that the lanthanide-SSSS-SSSS-M4DOTMA adopt the square antiprism (SAP) configuration at the beginning of the lanthanide series, but as the lanthanide ion size decreases across the series, the twisted square antiprism (TSAP) becomes more preferred. The late lanthanides adopted the TSAP geometry exclusively. The preference for the large lanthanides of SSSS-SSSS-M4DOTMA to adopt the SAP isomer is unprecedented for DOTA-type complexes. The NOE experiments together with the quantum chemical calculations at the level of density functional theory have indisputably demonstrated that the SAP of Pr-SSSS-SSSS-M4DOTMA and Pr-SSSS-SSSS-M8Spy as well as the TSAP of Yb-SSSS-SSSS-M8SPy are more stable than their corresponding isomers. For the large lanthanide ions (cerium – samarium), the rigidity of the ligand due to the SSSS-methyl substituents on both the arm and the ring causes the stronger methyl-methyl repulsion for the TSAP isomer, and thus favors the SAP isomer in solution.

Coordination isomer analysis of the lanthanide complexes of a rigidified polymethylated DOTA ligand

254th National Meeting (2017)

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