Pang Yuan-Ping
Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN, USA.
Commun Chem. 2022 Jan 20;5(1):9. doi: 10.1038/s42004-022-00624-4.
Cram's supramolecular capsule Octacid4 can irreversibly and noncovalently self-assemble with small-molecule guests at room temperature, but how they self-assemble and what accelerates their assembly remain poorly understood. This article reports 81 distinct Octacid4•guest self-assembly pathways captured in unrestricted, unbiased molecular dynamics simulations. These pathways reveal that the self-assembly was initiated by the guest interaction with the cavity portal exterior of Octacid4 to increase the portal collisions that led to the portal expansion for guest ingress, and completed by the portal contraction caused by the guest docking inside the cavity to impede guest egress. The pathways also reveal that the self-assembly was accelerated by engaging populated host and guest conformations for the exterior interaction to increase the portal collision frequency. These revelations may help explain why the presence of an exterior binding site at the rim of the enzyme active site is a fundamental feature of fast enzymes such as acetylcholinesterase and why small molecules adopt local minimum conformations when binding to proteins. Further, these revelations suggest that irreversible noncovalent complexes with fast assembly rates could be developed-by engaging populated host and guest conformations for the exterior interactions-for materials technology, data storage and processing, molecular sensing and tagging, and drug therapy.
克拉姆的超分子胶囊八酸4在室温下能与小分子客体不可逆地非共价自组装，但它们如何自组装以及是什么加速了组装过程仍知之甚少。本文报道了在无限制、无偏分子动力学模拟中捕获的81种不同的八酸4•客体自组装途径。这些途径表明，自组装始于客体与八酸4腔口外部的相互作用，以增加导致腔口扩张以供客体进入的腔口碰撞，并通过客体在腔内对接导致的腔口收缩来阻止客体逸出而完成。这些途径还表明，通过使丰富的主体和客体构象参与外部相互作用以增加腔口碰撞频率，自组装得以加速。这些发现可能有助于解释为什么酶活性位点边缘存在外部结合位点是乙酰胆碱酯酶等快速酶的基本特征，以及为什么小分子在与蛋白质结合时会采取局部最小构象。此外，这些发现表明，可以通过使丰富的主体和客体构象参与外部相互作用，为材料技术、数据存储和处理、分子传感和标记以及药物治疗开发具有快速组装速率的不可逆非共价复合物。
