Molecular Simulations On The Inclusions Of Cyclodecapeptides

Inclusions of cyclic peptides, a new host molecule, with many guest molecules are widely used in the field of molecular recognition. Like other host molecules, cyclopeptides have large cavity. Compared to some macrocyclic molecules of rigid structures such as cyclodextrins (CDs), crown ethers and calixarenes, there are good qualities for cyclopeptides. It’s easy for cyclopeptides to adjust an optimal conformation to interact with a small molecule owing to their conformational flexibility. The dynamical microscopic process with respect to the inclusion of guest molecule into cyclopeptide cavity can be predicted intuitively, the free energy change of inclusion system, structure characteristic and thermodynamic stability of inclusion complex at the minima of the free-energy profile can be revealed by using molecular simulation methods. These theoretical results will provide guidelines to related experiments.In this thesis, the glycine cyclodecapeptide [(Gly)10] and its modifications with a series of drug molecules with respect to binding patterns, structure characteristic and stability, free energy variation and driving force were studied, respectively, using molecular docking and molecular dynamics simulation methods. method. The main contents include:1. The inclusion actions were investigated in detail by the molecular docking techniques between (Gly)10and fifteen drug molecules; between ten modified compounds of (Gly)10and fifteen drug molecules, respectively. The results showed that these drug molecules can form inclusion complexes with glycine cyclodecapeptide and its modified compounds. The more aromaticrings of drug molecules were included, the higher binding energies were.2. The potential of mean force (PMF) methods were used to investigate microscopic process of molecular dynamics with respect to the inclusion of five drug molecules into (Gly)10cavity. The potential of mean force methods contain umbrella sampling (US) simulations and the weighted histogram analysis method (WHAM), and five drug molecules are Acetaminophen, Aminohippurate, Benzocaine, Mephentermine and R-Mexiletine. Free energy profiles along the reaction coordinates were obtained from PMF calculations for each inclusion system. The reaction coordinate for the US simulations was used as the distance of mass centers between (Gly)10and drug molecules. There is only one valley on the five PMF curves and all the profiles are qualitatively similar and exhibit a single shallow minimum. As the distance change between the reactions coordinates, there is a tendency that the free energy decreases at first and then increases. To investigate the thermodynamic stability of the complexes at the global minimum of the free-energy profiles,10ns molecular dynamics (MD) simulations were performed for inclusion structure at the minima. The results indicated that five inclusion structures at the minima of the free-energy profiles were stable within a10ns MD simulations.3. The microscopic process of molecular dynamics about two drug enantiomers,1-phenyl-1-propanol (MPP, M=R or S) and1-phenylpropan-2-amine (NPA, N=R or S), inclusion into glycine cyclodecapeptide modification [(Gly)9-Thr] cavity was investigated in detail using PMF methods. For the four inclusion systems of RPP, SPP, RPA, SPA with (Gly)9-Thr, the free energy profiles along the reaction coordinates were obtained from PMF calculations. The tendencies toward the free energies for the four PMF curves decrease at first and then increase. On the range of RPP, SPP, RPA, SPA inclusion into (Gly)9-Thr, it indicated that SPP with (Gly)9-Thr in free energy was significant lower than RPP; SPA with (Gly)9-Thr was slightly lower than RPA. Each inclusion structure at the minima of the four free-energy profiles was stable by additional10ns MD simulations. The studied results indicated that SPP exhibited the highest propensity to associate with (Gly)9-Thr.4. The five inclusion complexes of (Gly)10with Acetaminophen, Aminohippurate, Benzocaine, Mephentermine and R-Mexiletine were studied using molecular dynamics methods. The simulation conditions whether the five inclusion complexes are stable were explored. The results showed that (Gly)10with five drug molecules have stabilities only when they both have a restrictive force,0.5kcal·mol-1. On the one hand, this simulation condition can resist the flexibility and deformation of (Gly)10. On the other hand, drug molecules will not run along the (Gly)10cavity within the MD process and their binding patterns with (Gly)10will not change greatly. If (Gly)10have a restrictive force (0.5kcal·mol-1) but drug molecules not, Aminohippurate, Benzocaine and R-Mexiletine removed from (Gly)10cavity with simulations time. Although Acetaminophen and Mephentermine with (Gly)10have always inclusion action, the stabilities of two inclusion complexes are weak. Finally, MM_PBSA methods were used as binding energy calculations for (Gly)10with five drug molecules. The results indicated that van der waals energies and nonpolar solvation energies were the driving force for (Gly)10with five drug molecules.5. The six inclusion complexes about three drug enantiomers,1-phenyl-1-propanol,1-phenylpropan-2-amine and2-amino-N-(2,6-dimethylphenyl) propanamide, with (Gly)9-Thr were studied using molecular dynamics methods. The simulation conditions were also explored. The results manifested that (Gly)9-Thr with three enantiomers have stabilities only when they both have a restrictive force,0.5kcal·mol-1. Binding energy calculations by MM_PBSA methods indicated that van der waals energies and nonpolar solvation energies were the driving force for (Gly)9-Thr with three enantiomers.