Rigidified and Hydrophilic DOTA-like Lanthanoid Ligands: Design, Synthesis, and Dynamic Properties.

Area of Science:

• Biophysical Chemistry
• Chemical Biology
• Structural Biology

Background:

• Paramagnetic Nuclear Magnetic Resonance (NMR) is a powerful technique for determining protein structures.
• Accurate structural information relies on limiting the dynamics of paramagnetic tags.
• Existing paramagnetic tags can suffer from excessive flexibility, limiting their utility.

Purpose of the Study:

• To design and synthesize a novel hydrophilic, rigid lanthanoid complex for paramagnetic NMR.
• To investigate the conformational dynamics of the new complex and compare it to existing DOTA derivatives.
• To assess the suitability of the new complex as a rigid probe for protein NMR.

Main Methods:

• Synthesis of a novel DOTA-like lanthanoid complex with a C2 symmetric macrocyclic ring and four chiral hydroxyl-methylene substituents.
• Nuclear Magnetic Resonance (NMR) spectroscopy, including 2D 1H exchange spectroscopy, to study conformational dynamics.
• Comparison of the novel complex's dynamics with DOTA and its derivatives using Europium complexation.

Main Results:

• The novel complex exhibits a twisted square antiprismatic conformation preferentially over the square antiprismatic form, differing from DOTA.
• Ring flipping of the cyclen ring is suppressed by the four chiral equatorial substituents.
• Suppressed ring flipping leads to slower reorientation of pendant arms and coordination arms, indicating reduced dynamics.
• The hydrophilic nature of the complex is expected to reduce protein precipitation.

Conclusions:

• The designed hydrophilic lanthanoid complex demonstrates significantly reduced conformational dynamics.
• The suppressed ring flipping and slower arm reorientation make it an excellent scaffold for developing rigid probes for paramagnetic NMR.
• This new class of complexes offers potential for improved structural studies of proteins without causing precipitation.