Sandilya Avilasha A, Natarajan Upendra, Priya M Hamsa
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai 600036, India.
ACS Omega. 2020 Aug 27;5(40):25655-25667. doi: 10.1021/acsomega.0c02760. eCollection 2020 Oct 13.
We find, through atomistic molecular dynamics simulation of native cyclodextrins (CDs) in water, that although the outer surface of a CD appears like a truncated cone, the inner cavity resembles a conical hourglass because of the inward protrusion of the glycosidic oxygens. Furthermore, the conformations of the constituent α-glucose molecules are found to differ significantly from a free monomeric α-glucose molecule. This is the first computational study that maps the conformational change to the preferential hydrogen bond donating capacity of one of the secondary hydroxyl groups of CD, in consensus with an NMR experiment. We have developed a simple and novel geometry-based technique to identify water molecules occupying the nonspherical CD cavity, and the computed water occupancies are in close agreement with the experimental and density functional theory studies. Our analysis reveals that a water molecule in CD cavity loses out about two hydrogen bonds and remains energetically frustrated but possesses higher orientational degree of freedom compared to bulk water. In the context of CD-drug complexation, these imply a nonclassical, that is, enthalpically driven hydrophobic association of a drug in CD cavity.
通过对天然环糊精（CDs）在水中进行原子分子动力学模拟，我们发现，尽管CD的外表面看起来像一个截顶圆锥体，但由于糖苷氧向内突出，其内腔类似一个锥形沙漏。此外，发现组成α-葡萄糖分子的构象与游离单体α-葡萄糖分子有显著差异。这是第一项将构象变化与CD二级羟基之一的优先氢键供体能力进行映射的计算研究，与核磁共振实验结果一致。我们开发了一种简单新颖的基于几何的技术来识别占据非球形CD腔的水分子，计算得到的水占有率与实验和密度泛函理论研究结果非常吻合。我们的分析表明，CD腔内的一个水分子失去了大约两个氢键，能量上仍处于受阻状态，但与 bulk水相比具有更高的取向自由度。在CD-药物络合的背景下，这些意味着药物在CD腔内存在非经典的、即焓驱动的疏水缔合。
