| The Ru(III)-based anticancer agents have been the most promising metallodrugs for their lower general toxicity and higher anti-drug resistance activity than platinum metallodrugs.Due to the development of synthetic chemistry for metal-containing pharmaceuticals,many Ru(III)-based complexes have been synthesized and tested for antitumor activity.However,the anticancer mechanism of the ruthenium complexes remains ambiguous,investigation of the reaction mechanism of ruthenium complexes particularly at the molecular level is helpful for its clinical research and discovering new metal based drugs with grateful anticancer properties and lesser side effect.Nowadays,the combined quantum mechanical/molecular mechanical(QM/MM)method has been successfully applied to a wide range of reactions in solution.In this work,ABEEM??(atom-bond electronegativity equalization method)fluctuating charge polarizable force field combined with QM[QM/MM(ABEEM)]has been employed to investigate the hydrolysis mechanism of NAMI-A and ICR,and the interaction mechanism of NO with hydrolysates of NAMI-A.The results shows that QM/MM(ABEEM)can reasonably describe the reaction path,and the activation free energies which obtained by the combined QM/MM(ABEEM)method and molecular dynamics-free energy perturbation(MD-FEP)method are in agreement with experimental results.Moreover,the interactions between hydrolysates of NAMI-A and histidine or guanine have been investigated by QM method.1)Combined QM/MM(ABEEM)with MD-FEP method study on the hydrolysis reaction mechanism of NAMI-AEleven possible reaction paths have been uncovered by QM/MM(ABEEM)method up to the fourth hydrolysis steps of NAMI-A.Structures which on the minimum energy reaction path have been optimized by QM/MM(ABEEM)method and the activation free energies were obtained by combined QM/MM(ABEEM)with free energy perturbation theory.Based on analysis of structures and activation free energies,the hydrolysis rate of DMSO is faster than Cl-ligand in the first step,which is accordant with experimental results.Activation free energies of the reaction paths in the second hydrolysis step are lower than that of the first hydrolysis step,but the trans-position Cl-hydrolysis in the second step takes more time to perform.Our reaults can account for experimental phenomenon reasonably.Both Cl-ligand and DMSO ligand can be replaced by H2O molecule in the third hydrolysis step and[Ru Cl(H2O)4(Im)]2+is the main solute in aqueous solution after the fourth hydrolysis step.It demonstrates that QM/MM(ABEEM)is a promising method for studying chemical reactions in aqueous solution,and the hydrolysis mechanism of NAMI-A has been clarified reasonably.2)Interaction mechanism of hydrolysates of NAMI-A with NO:a detail theoretical investigation by QM/MM(ABEEM)methodThe interactions of NO with NAMI-A hydrolysates have been investigated both in the triplet spin state and in the singlet spin state in this work.Activation free energies were calculated by the combined QM/MM(ABEEM)method with MD-FEP.Our results indicate that the ruthenium-nitrosyl complexes formed by NO interacting with Ru(III)may have two forms:[RuIII-NO]and[RuII-NO+].The Ru-N-O angle of the triplet ruthenium nitrosyl complexes is in the range of 135.6°-138.4°.However,all the singlet ruthenium nitrosyl complexes show an almost linear Ru-N-O angle.All Ru-N(NO)bonds in the triplet ruthenium nitrosyl complexes are longer than that in the singlet ruthenium nitrosyl complexes.Both the first step and the the second step hydrolysates of NAMI-A can interact with NO in solution.The rate of nitrosylation reactions is faster than that of further hydrolysis reactions for the first step hydrolysates of NAMI-A.Thus,the nitrosylation reaction can occur prior to the hydrolysis reaction for the first step hydrolysates.Activation free energies of the hydrolysis reactions of ruthenium nitrosyl complexes show that the rate of DMSO-H2O exchange reaction of[Ru Cl3(NO)(Im)(DMSO)]is faster than that of[Ru Cl3(H2O)(Im)(DMSO)],but the hydrolysis reactions of the other ruthenium nitrosyl complexes may not occur in solution.3)ABEEM??fluctuating charge polarizable force field combined with QM and MD-FEP---Hydrolysis reaction of anticancer ruthenium drug ICRIn order to simulate the hydrolysis reaction of ICR in the realistic explicit solvent environment,the calculation of MM region in QM/MM method has been performed by ABEEM??fluctuating charge polarizable force field.By comparing the structures obtained by QM,PCM and QM/MM(ABEEM)method,the results indicate that the structures optimized by QM/MM(ABEEM)method are reasonable.The activation free energy has been calculated by PCM,QM/MM(ABEEM)and QM/MM(OPLS-AA)methods,respectively.The result obtained by QM/MM(ABEEM)has a good agreement with the experimental value.The systems consisted of IRC molecule with adding 1,2,3,4,8,12 and 20 water molecules were set as QM region,respectively.When there are twenty water molecules in QM region,the corresponding activation free energy obtained by QM/MM(ABEEM)of this hydrolysis reaction is fairly in line with the experimental value.4)Interaction of hydrolysates of NAMI-A with histidine(His)and guanine(G):a detail theoretical investigationThe interaction mechanisms of seven hydrolysates of NAMI-A with His and G have been investigated by DFT method and PCM model.If the location or number of water ligand in ruthenium complex differs from each other,the interaction of the complexes with His or G must be different.It has been testified that our method can be used for the further investigation of the interaction between the Ruthenium complexes and protein or DNA.The rates of the ligand exchange reactions for hydrolysates of NAMI-A with G are faster than that with His.The activation free energies of the axil H2O ligand exchange reactions of the second step hydrolysate[Ru Cl3(H2O)2(Im)]are lower than the other hydrolysates.[Ru Cl2(H2O)3(Im)]and[Ru Cl(H2O)4(Im)]are also the active hydrolysates which can bind to G.So we can say that the futher hydrolysis reactions of NAMI-A are very important for its anticancer activity,the diaqua complexes formed by DMSO and Cl-dissociation are kinetically suprior to other hydrolysates.Our results indicate that steric effect and hydrogen bonds play key roles in affecting the reactions. |
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