Synthesis and Properties of Dodecyl Trehaloside Detergents for Membrane Protein Studies

Sugar-based detergents, mostly derived from maltose or
glucose,
prevail in the extraction, solubilization, stabilization, and crystallization
of membrane proteins. Inspired by the broad use of trehalose for protecting
biological macromolecules and lipid bilayer structures, we synthesized
new trehaloside detergents for potential applications in membrane
protein research. We devised an efficient synthesis of four dodecyl
trehalosides, each with the 12-carbon alkyl chain attached to different
hydroxyl groups of trehalose, thus presenting a structurally diverse
but related family of detergents. The detergent physical properties,
including solubility, hydrophobicity, critical micelle concentration
(CMC), and size of micelles, were evaluated and compared with the
most popular maltoside analogue, β-d-dodecyl maltoside
(DDM), which varied from each other due to distinct molecular geometries
and possible polar group interactions in resulting micelles. Crystals
of 2-dodecyl trehaloside (2-DDTre) were also obtained in methanol,
and the crystal packing revealed multiple H-bonded interactions among
adjacent trehalose groups. The few trehaloside detergents were tested
for the solubilization and stabilization of the nociceptin/orphanin
FQ peptide receptor (ORL1) and MsbA, which belong to the G-protein
coupled receptor (GPCR) and ATP-binding cassette transporter families,
respectively. Our results demonstrated the utility of trehaloside
detergents as membrane protein solubilization reagents with the optimal
detergents being protein dependent. Continuing development and investigations
of trehaloside detergents are attractive, given their interesting
and unique chemical–physical properties and potential interactions
with membrane lipids.