Molecular Modeling On Recognition Of Wobble DNA By Polypyridine Chiral Metal Complexes

The duplex-helix structure of DNA with Watson-Crick base pairs of G.C and A:T are important carrier of storing, expressing and transferring genetic information. This special base matching form is useful to stabilize nucleic acid structure. The distribution of functional groups in major and minor groove are propitious to the interaction between DNA and protein enzyme, metal ion and metal complex with biological functional. DNA replication must be very accurate in order to pass genetic information to next generation exactly. But the human gene includes about 10⁹ base pairs and in replicating process, its duplex helix structure may be destroyed easily by any physical or chemical action that may lead to base mismatching, non-pairing, rupture of DNA chain and so on.In recent years, people studied the interaction between polypyridine transitional metal complex and DNA more deeply, and it has been a very active subject in bioinorganic chemistry field. The octahedron polypyrimidine ruthenium(II) complex was extensively used as DNA structural probe, photic switch, cleavage reagent and electron transition that was conducted by DNA. These micromolecules, which could specially recognize DNA, lay a solid foundation for gene choosing new medicine.In this work, we studied the interaction between some polypyridine metal complexes and mismatched DNA with molecular modeling method. So we could discuss their mechanism of action in molecular level. We have already successfully simulated the recognition interaction of some chiral metal complex to normal B-DNA and sheared DNA including G:A mismatches. This time, we would study some extensively applied polypyridine metal complexes to recognize wobble DNA including G:T mismatches, such as [Ru(phen)₂(hpip)]²⁺ , [Ru(phen)₂(dpq)]²⁺ ,[Ru(phen)2(dppz)] ^ [Ru(IP)2(dppz)] . We reviewed the system energy in all action process, analysed the detailed interaction and gave some rational explanation to simulation results.Concretely, my study mainly included four parts below:1 -, Molecular Modeling on the Recognition of Wobble DNA Including G:T Mismatched Pairs by Two Structures of Chiral Metal Complex A, A-[Ru(phen)2hpip]2+: [Ru(phen)2hpip]2+ has two kinds of vibrational structures and their energy difference could be applied by environment in room temperature. So we must consider the difference of recognition results brought by it. The results revealed that all of the four chiral isomers of the two structures could recognize the mismatched DNA from the minor groove orientation especially and the interaction was enantioselective and sitespecific. The two left isomers were more preferential than the right ones. Especially, the structure II whose energy was much lower after interacting DNA was the advantaged structure. Detailed energy analysis indicated that the steric interaction in the process of the complex inserting base stacking determined the recognition results and the electrostatic interaction made an effect in some extent.2^ Molecular simulation on the recognition and partial structural repair of cyclobutane pyrimidine dimer including double G:T mismatched pairs by the chiral metal complex A ^ A -[Ru(phen)2dpq]2+: The cyclobutane pyrimidine dimer (CPD) is the chief tache when ultraviolet ray damages DNA that could lead to skin cancer. The cycloaddition happened between thymine and its neighboring pyrimidyl base (T or C) that was in the same chain. At last, the CPD formed. There were two neighboring G bases in it complementary chain. So G:T mismatch increased the stability of CPD and it is important to recognition CPD. But the inserting ligand dpq was too short and its plane area was too small, additionally the DNA helix distorted seriously. So the recognition process did not show any better stereoselectivity and sitespecifity. In all, [Ru(phen)2dpq]2+ was not suitable to use asrecognition reagent of CPD including double G:T mismatched pairs in wobble DNA.3 ? Molecular simulation on the recognition and partial structural repair of cyclobutane pyrimidine dimer including double G:T mismatched pairs by the chiral metal complex A , A -[Ru(phen)2dppz]2+: Dppz has a much bigger plane area and it is longer than dpq. Its symmetry characteristic was quite well. The results revealed that the left isomer of the complex chose minor groove optimally to recognize the A4T5/T7G6 site next to the CPD and the right isomer chose major groove optimally to recognize the T6A7/G5T4 site bordering upon the other side of CPD. The DNA double helix was distorted seriously because of the existence of CPD. But the interaction was still enantioselective and site-specific and the left isomer was much more optimal compared with the right one. Detailed energy analysis indicated that the steric interaction in the process of the complex inserting to base stacking determined the recognition results and the electrostatic interaction made an effect in some extent. Additionally, we found that the shape of two T bases forming CPD changed from mouth shape to approximate parallel shape after the complex intercalating DNA. That was the initial conformational repair. So, the A -[Ru(phen)2dppz]2+ could be used as CPD's recognizing reagent.4^ Molecular simulation on the recognition and partial structural repair of cyclobutane pyrimidine dimer including double G:T mismatched pairs by the chiral metal complex A ? A -[Ru(IP)2dppz]2+: [Ru(IP)2dppz]2+ had been validated by experiment that it could interact with calf thymus DNA strongest. Through molecular mechanics simulation, we found it could bind with CPD wobble DNA stronger than [Ru(phen)2dppz]2+. The recognition process showed obvious stereoselectivity and sitespecifity. The left isomer of the complex chose minor groove optimally to recognize the A4T5/T7G6 site next to the CPD and the right isomer chose major groove optimally to recognize the T6A7/G5T4 site bordering upon the other side of CPD. We also found that the shape of two T bases forming CPD changed from mouth shape toapproximate parallel shape after the complex intercalating DNA. That was the initial conformational repair. Relatively, the A -[Ru(IP)2dppz]2+ was more optimal than the right isomer. So, the A -[Ru(IP)2dppz]2+ was the better recognizing reagent.Comparation on the recognition of three complexes [Ru(phen)2(dpq)]2\ [Ru(phen)2(dppz)]2+ and [Ru(IP)2(dppz)]2+ to cyclobutane pyrimidine dimer including double G:T mismatched pairs, we obtained some useful information that could not been given by experimental methods. [Ru(phen)2(dppz)]2+ and [Ru(IP)2(dppz)]2+ could recognize CPD specilly, but their interaction were little different. The main factors leading to difference include electrostatic and steric interaction of DNA helix and the shape of complex probe.