Study On The Structures And Properties Of Charybdotoxin By Using The Ab Initio Method And ABEEMσπ Model

Molecular recognition between peptide blockers and ionic channels is a complex process that involves many effects.In this thesis,the structures of the ChTX and six of its mutants,amino acid residues of its active regions and the side chains of these amino acid residues were chosen as the models.A theoretical study of chemical reactivity analysis of these proteins was carried out by using global reactivity descriptors.The structures of the ChTX and six of its mutants and amino acid residues of its active regions were taken from the Protein Data Bank.And the structures of the side chains molecules of these amino acid residues were optimized by B3LYP/6-311++G（d,p）in Gaussian09.Then some parameters of ABEEMσπmodel（valence-state electronegativity,valence-state hardness）were calibrated by linear regression and least squares optimization procedure.ABEEMσπmethod was used to calculate the charge distributions of these systems mentioned above.The slope of the linear correlation equation of the charge distribution between ABEEMσπmethod and HF/STO-3G ab initio is close to 1.07,the intercept is close to 0.001,and the linear correlation coefficient is over 0.97.Therefore,the results which calculated by ABEEMσπmethod are in accordance with those by ab initio method.It can be demonstrated that the ABEEMσπparameters are suitable and transferable.And they will be used to calculate the charge distributions of the similar systems.The global softness and global electrophilicity of these proteins were calculated by using ab initio method and ABEEMσπmodel.According to Hammett relationship equation,coefficients about the global softness and electrophilicity were calculated.We have explored the relationship of Hammett coefficients of ChTX proteins with the dissociation kinetic constants between the ChTX proteins K⁺channel.The results show that these global softness and electrophilicity have a correlation with the ChTX–channel interactions.The smaller global softness,the greater dissociation kinetic constants between the ChTX proteins K⁺channel.Kinetic studies of the reaction using mutants of ChTX,have shown that crucial amino acids for the activity of the toxin alter the kinetics of the ChTX–channel interactions,mainly through increasing the dissociation constant,k_off.At the same time,the global softness of wild-type ChTX is the smallest,when the dissociation kinetic constant between K⁺channel and the ChTX is the greatest.In addition,ABEEMσπmodel is an important tool for us to obtain some properties about the toxin,which can be used to discuss the relationship between the dissociation kinetic constants and the ChTX and six of its mutants.