Aggregate Structures Of Quinacridone Derivatives And HCTR1-TMD2 Studied By Theoretical Calculation

The work of this thesis is mainly divided into two parts. The first part is aboutstudy of the intermolecular - stacking interaction of the dimers of quinacridonederivatives (QAs) by theoretical calculation. We used DFT-D method to calculate thebinding energies of the QA dimers at several main stacking configurations andobtained the most stable structures. Furthermore, we explored the influences ofsubstituents on the strength of - stacking interactions. The second part is thestructural study of the trimer composed of the transmembrane domain 2 of hCTR1 inPOPC lipid bilayer by molecular dynamics simulation.Nonconvalent interactions have a widespread importance to so many areas ofchemistry, biology, and materials science, and until today they are still an importanttopic of study. Moreover, a clear understanding of such interactions is indispensablefor the rational design of new drugs and organic materials. Unfortunately, at present,many basic properties of noncovalent interactions, particularly those involving system, remain unknown. Because intermolecular - stacking interaction is a weakinteraction and the binding energy is very small, experiments aimed at elucidating thedetails of - interaction face a number of serious obstacles. The structure is notdirectly observable and stabilization energy is hard to be extracted from experimentalmeasurements due to small binding energy (²-3 kcal/mol for benzene dimer in gasphase) and anharmonicity of - interactions. At this moment, we have to resort to themethod of theoretical calculation. A significant advantage of computational studies isthat one can directly study prototype systems of interest in the absence of othercompeting interactions and solvent effect.We used fiveN,N′-dimethyl quinacridone derivatives as model molecules, whichare denoted as QA-C₁, DF-QA-C₁, DM-QA-C₁,TM-QA-C₁, and TF-QA-C₁to study the - stacking interaction of their dimers by DFT-D computation. We calculated thepotential energy curves of PS, PD, APS, APD, r-APS, r-APD and s-PD configurationsof these QA dimers at the B97-D/6-31+G* level and obtained the most stablestructure of each dimeric configuration. By energy comparison, we found that theparallel stacking configurations (PS and PD) are less stable than the antiparallelconfigurations (APS and APD), and the type of APD configurations (APD and r-APD)is more stable than the type of APS configurations (APS and r-APS) for all QA dimers.The Boltzmann factors were calculated for the four antiparallel configurations ofQA-C₁/QA-C₁dimer at 25 and the ratio of the Boltzmann factors for these types ofconfigurations are APS:r-APS:APD:r-APD=1:2.6:5.9:6.5. Compared withr-APS/APS configuration, the r-APD/APD configurations have a greater populationand lower interaction energy, which may explain why the observed configurations ofQA dimers are mainly antiparallel-displaced structures in solution by NMRexperiment. The electrostatic compensation of the electron-rich carboxyl oxygenatoms with the electron-poor nitrogen atoms determines the preferentialconfigurations of the QA dimers. No matter the substituents at the side aromatic ringare electron-donating (CH₃) or electron-withdrawing (F), they tend to enhance the - stacking interaction of QA dimers. The former provides more dispersion interactionand the latter decreases the exchange-repulsion interaction for the - stacking ofaromatic rings. The binding energy of mixed-type quinacridone derivatives is betweenthe binding energy of dimers which are self-assembled by two monomers.Comparedwith CH₃substituent QAs, F substituent QAs form mixed-type dimers with QA-C₁more easily in the same condition including substituent number and substituentposition. F atomics have electron-withdrawing effect, which will lead to reduce theenergy of electrostatic repulsionbetween aromatic rings. Methyl substituents induceincreasing in the energy of dispersion. All these effects will enhance the - stackinginteraction of mixed-type QAs dimers at the same time. If the substituents are all ofelectron-withdrawing or electron-donating, the more number of substituents, thegreater binding energy, and the better structural stability. This study may provide moreinsights into the nature of - stacking interaction. Human copper transporter 1 (hCTR1) is a high-affinity copper transport protein.It exists in mammalian cell membranes and is responsible for the absorption andutilization of copper. It was demonstrated that hCTR1 is not only involved in themetabolism process of copper ion, but also involved in the uptake of several platinumantineoplastic drugs. This protein contains 190 amino acids including threetransmembrane-spanning domains, an extracellular N terminus and intracellular Cterminus domains. The hCTR1 is trimerized in lipid membranes and the trimerichCtr1 contains a pore. In the three transmembrane domains, the TMD2 constructs theinner wall of pore and may participate in copper ion transfer directly. Therefore, theaggregate structure of TMD2 plays an important role in the biological function. Thestudy on the trimeric structure of TMD2 may reveal the mechanism of the transfer ofcopper ion. Therefore, we performed the molecular dynamics simulation of thetrimeric structure of TMD2 in POPC bilayer. The results show that hCTR1-TMD2trimer forms a pore in POPC bilayer and all hydrophilic residues in each monomericunit locate in the inside of the pore, and the trimer is inclined in the bilayer in order todecrease the hydrophobic mismaching.