Department of Chemistry and Biochemistry, and Advanced Materials and Liquid Crystal Institute, Kent State University, Kent, Ohio 44242, United States.
Department of Mechanical and Aerospace Engineering, The George Washington University, Washington, District of Columbia 20052, United States.
J Phys Chem B. 2021 Oct 14;125(40):11112-11121. doi: 10.1021/acs.jpcb.1c03916. Epub 2021 Sep 15.
Biological host molecules such as β-cyclodextrins (β-CDs) have been used to remove cholesterol guests from membranes and artery plaques. In this work, we calibrated the host-guest intermolecular mechanical forces (IMMFs) between cholesterol and cyclodextrin complexes by combining single-molecule force spectroscopy in optical tweezers and computational molecular simulations for the first time. Compared to native β-CD, methylated beta cyclodextrins complexed with cholesterols demonstrated higher mechanical stabilities due to the loss of more high-energy water molecules inside the methylated β-CD cavities. This result is consistent with the finding that methylated β-CD is more potent at solubilizing cholesterols than β-CD, suggesting that the IMMF can serve as a novel indicator to evaluate the solubility of small molecules such as cholesterols. Importantly, we found that the force spectroscopy measured in such biological host-guest complexes is direction-dependent: pulling from the alkyl end of the cholesterol molecule resulted in a larger IMMF than that from the hydroxyl end of the cholesterol molecule. Molecular dynamics coupled with umbrella sampling simulations further revealed that cholesterol molecules tend to enter or leave from the wide opening of cyclodextrins. Such an orientation rationalizes that cyclodextrins are rather efficient at extracting cholesterols from the phospholipid bilayer in which hydroxyl groups of cholesterols are readily exposed to the hydrophobic cavities of cyclodextrins. We anticipate that the IMMF measured by both experimental and computational force spectroscopy measurements help elucidate solubility mechanisms not only for cholesterols in different environments but also to host-guest systems in general, which have been widely exploited for their solubilization properties in drug delivery, for example.
生物宿主分子，如β-环糊精（β-CDs），已被用于从膜和动脉斑块中去除胆固醇客体。在这项工作中，我们首次结合单分子力谱光学镊子和计算分子模拟，校准了胆固醇与环糊精复合物之间的主客体分子间力学力（IMMFs）。与天然β-CD 相比，与胆固醇络合的甲基化β-环糊精由于甲基-β-CD 腔体内更多高能水分子的损失，表现出更高的机械稳定性。这一结果与甲基-β-CD 比β-CD 更能溶解胆固醇的发现一致，表明 IMMF 可以作为评估胆固醇等小分子溶解度的新指标。重要的是，我们发现此类生物主客体复合物中的力谱测量是有方向依赖性的：从胆固醇分子的烷基端拉动会导致更大的 IMMF，而从胆固醇分子的羟基端拉动则会导致较小的 IMMF。分子动力学结合伞状采样模拟进一步揭示了胆固醇分子倾向于从环糊精的宽开口进入或离开。这种取向可以解释为什么环糊精能够从胆固醇的羟基基团容易暴露于环糊精的疏水性腔中的磷脂双层中有效地提取胆固醇。我们预计，实验和计算力谱测量所测量的 IMMF 不仅有助于阐明不同环境中胆固醇的溶解度机制，而且有助于阐明一般的主客体系统的溶解度机制，这些系统在药物输送等方面因其溶解性质而被广泛利用。
