Theoretical Investigation On Stable Conformations And Shuttling Processes Of Rotaxanes

Rotaxanes are mechanically interlocked molecular complexes. They have two or more stable conformations. The shuttling processes can transform from one conformation to another one. Those unique properties make rotaxanes promising candidates ranging from molecular devices to drug carriers. However, incomplete knowledge about those properties of rotaxanes blocks their further improvements. In this dissertation, stable conformations and shuttling processes of two rotaxanes were investigated with the aid of molecular dynamics simulations and free energy calculations to shed lights on key factors contributed to stable conformations and driving forces underlying shuttling processes. The main contents of the present dissertation include:(1) Molecular necklaces are one kind of [n]rotaxanes, which are formed by n-1a-cyclodextrins (a-CDs) threaded onto one poly(ethylene glycol) chain. Those necklaces have been envisioned to hold great promise as drug carriers and gene vectors. Their function depends intimately on their stable conformations. Here, molecular dynamics simulations, free-energy calculations, and lattice chain Monte Carlo simulations have been applied to explore this CD-based rotaxane. Stable conformations have been obtained. The results are consistent with experiments. Meanwhile, the methods used in this chapter are expected to help investigate other one dimentional chemical or biological self-assembly processes.(2) Rotaxanes are composed by a linear molecule with stoppers at both termini and a macrocycle, i.e.,α-CD, threaded onto the latter. This macrocycle can shuttle between two or more stations connected by linkers under external stimuli. Here, molecular dynamics simulations combined with free-energy calculations have been applied to investigate a CD-based rotaxane. The free-energy profile characterizing the shuttling process of the CD along the molecular thread was determined and partitioned into tcontributions of different nature. The underlying molecular mechanism of the shuttling process has been deciphered. The present results rationalize experimental observations, and provide the theoretical basis for the investigataion of solvent-driven shuttling processes.(3) The shuttling process of rotaxanes driven by solvents can greatly facilitate translocation of drugs across the plasma membrane. Here, molecular dynamics simulations combined with free-energy calculations have been applied to investigate a rotaxane drivened by solvent and temperature. The free-energy profiles delineating the shuttling processes of this rotaxane in different environments have been drawn. The underlying shuttling mechanism and driving force were obtained. The results match well with experimental measures, and pave the way for further investigation aimed at understanding the working mechanism of rotaxane-based drug carriers.(4) Free-energy perturbation (FEP) is one of the most commonly chosen approaches for tackling transformations of a chemical process between two or more thermodynamic states. To augment the accuracy, the precision, and, hence, the reliability of these calculations, a number of good practices have been established. Here, a plugin, coined ParseFEP, was proposed to follow these prescriptions in a user-friendly environment. Written as a Tcl plugin, it allows FEP calculations carried out using the popular molecular-dynamics package NAMD to be analyzed seamlessly within the visualization platform VMD. The potential of this plugin is probed through a number of illustrative examples, which demonstrate cogently how pathological cases, often related to convergence issues, can be detected and remedied by means of a pictorial approach.