Direct Measurement of Intermolecular Mechanical Force for Nonspecific Interactions between Small Molecules

Mechanical force can evaluate intramolecular interactions in macromolecules. Because of the rapid motion of small molecules, it is extremely challenging to measure mechanical forces of nonspecific intermolecular interactions. Here, we used optical tweezers to directly examine the intermolecular mechanical force (IMMF) of nonspecific interactions between two cholesterols. We found that IMMFs of dimeric cholesterol complexes were dependent on the orientation of the interaction. The surprisingly high IMMF in cholesterol dimers (similar to 30 pN) is comparable to the mechanical stability of DNA secondary structures. Using Hess-like cycles, we quantified that changes in free energy of solubilizing cholesterol (Delta G(solubility)) by beta-cyclodextrin (beta CD) and methylated beta CD (Me-beta CD) were as low as -16 and -27 kcal/mol, respectively. Compared to the Delta G(solubility) of cholesterols in water (5.1 kcal/ mol), these values indicated that cyclodextrins can easily solubilize cholesterols. Our results demonstrated that the IMMF can serve as a generic and multipurpose variable to dissect nonspecific intermolecular interactions among small molecules into orientational components.

Automated summary

The study used optical tweezers to directly investigate the intermolecular mechanical force of nonspecific interactions between cholesterols, revealing that the IMMF of cholesterol dimers is orientation-dependent. Quantification of changes in free energy showed that cyclodextrins can easily solubilize cholesterols.