超分子主客体结构与分子识别机理的理论研究

Host-guest chemistry is the main branch of supramolecular chemistry, the main driving force is the intermolecular interactions. Cucurbit[n]urils (CB[n]) are a family of macrocyclic host molecules, they has been widely used in drug delivery, catalysis, biosensor, nanotechnology and so on and become potential host materials, due to their easy synthesis, functionalization and highly host−guest binding strength and selectivity. Experimental investigations indicate that small-sized CB[n] has a good binding affinity with amino acids and peptides, while large-sized CB[n] could encapsulate small organic molecules and form 1:1 binary complexes or 2:2 quaternary complexes and the binding motifs of host-guest interactions depend on substituents of guests: electron-withdrawing or electron-donating. However, the intrinsic mechanism of the molecular recognition at a molecular level is still unclear.. In this project, we will systematically investigate the molecular recognition mechanism of CB[n] and the fundamental amino acids, their representative derivatives as well as small organic molecules, by combining the quantum chemistry and molecular dynamics simulations, to explore the dependence of the binding mode, the binding pathway and the binding affinity of CB[n]-based host-guest interactions on substitutions in guest molecules. In addition, we will explicitly provide the relative contributions of each non-covalent interaction to the binding energies of host-guest interactions. Finally, we will unravel the intrinsic mechanism of CB[n]-based molecular recognition to help experimentalists rational molecular design of host-guest systems. The research value of this project is 1) to explain the experimental phenomenon and to fill the experimental blank; 2) to provide the theoretical evidence for the rational design of novel host-guest molecular recognition material; 3) to promote the theoretical investigation of intrinsic mechanism of molecular recognition.

主客体化学是超分子化学的重要分支，其主要驱动力是分子间非共价键相互作用。葫芦脲（CB[n]）是一类大环超分子主体，因其易合成易功能化且有较强主客体结合选择性而成为热门的主体材料，被应用于药物输运、催化、生物探针和纳米科技等领域。实验研究发现小空腔CB[n]对氨基酸、多肽有较高识别性能，大空腔CB[n]能和有机分子形成1:1或2:2型主客体配合物，其结合模式和结合自由能由取代基的推拉电子能力决定，但其内在机制仍不清楚。.本项目将量子化学与分子动力学模拟相结合，系统研究CB[n]与氨基酸及其衍生物的主客体分子识别，探索主客体配合物结合模式、结合路径、结合自由能及各种弱相互作用与取代基的内在联系，揭示CB[n]类主客体分子识别内在机理，并辅助实验进行分子设计。其研究价值在于：解释实验现象，填补实验空白；为合理设计新型主客体分子识别材料提供理论依据；促进主客体分子识别理论研究的发展。

本研究将量子力学（Quantum Mechanism, QM）与分子动力学（Molecular Dynamics, MD）模拟相结合，系统研究CB[7]与氨基酸及短肽间的主客体分子识别过程，探索主客体配合物结合模式、结合自由能及各种弱相互作用的相对贡献，揭示主客体分子识别的内在机理。所得计算结果不仅有助于理解错综复杂的实验现象，且为合理设计新型主客体分子识别材料和性质可调的发光材料提供理论依据。主要研究结果概括如下：（1）与中性氨基酸相比，质子化可在主客体间额外引入离子-偶极相互作用，增强主客体结合强度。以Phe为N端设计的三肽体系中，CB[7]与三肽FGE、FGK、FGR的分子识别可达纳摩尔级别。CB[7]能够用于区分结构相似的WGR和WGK，仅把C-端的R变成具有相似侧链的K，其结合亲和性能相差8个数量级。（2）多重主客体相互作用（包括疏水作用、氢键和O-H…π）能够协同驱动形成AIEgen的主客体复合物，从而增大激发态辐射跃迁速率常数，减小重整能，使荧光增强。聚集体形成后，聚集效应与主客体相互作用协同，能进一步有效抑制激发态的无辐射衰减通道，增强荧光发射。与此同时，我们提出TTPy和TTVP的发光由疏水部分和吡啶环共同决定，而其穿膜能力则有亲水部分的带电基团决定。因此，我们提出设计两亲性AIEgen以选择性“点亮”线粒体和细胞膜的策略，并被细胞成像实验验证。（3）最后，我们提出薄层P4O2（α-3）、夹心P4O2/BP体系（O-1-P）以及横向异质结构AlP3-GaP3三种潜在的光催化分解水材料。..在本项目的资助下，共发表16篇SCI学术论文，其中一篇刚发表在Angew. Chem. Int. Ed.上的文章还未被SCI收录。