Mechanism And Regulation Of Metal Ion Induced Protein Aggregation

This study carry out optimization, frequence and single-point calculations for thecomplexes of26kinds of protein peptide chain structures （T1-26） as well as two drugmolecules （Y₁，Y₂） binding, respectively, with Cu2⁺、Cu⁺and Zn²⁺at the M06/6-31+G**levelof Gaussian09. Then solvent effect is considered by usint Polarizable Continuum Model（PCM） solvent model and the radius used is the default radius of UAO. Meanwhile, adiabaticbinding energy and deformation energy and charge distribution are also discussed. Theaggregation mechanism of peptide and the regulation effect of drug molecules are given. Asgene mutations can also cause aggregation, we use four different methods to study thestability of complexes formed by13kinds of cytosine C isomers, respectively, binding Na⁺,K⁺, Ca²⁺, Mg²⁺metal ions in the gas and liquid phases. By the study, we can examine theimpact of the base isomerization caused of metal ion binding.The minimum of the adiabatic binding energy ΔEbaof Cu⁺-T（Y） in the gas phase is Cu⁺--T19, while the maximum is Cu⁺-T17. Y1is better than Y₂to inhibit the aggregation of theprotein peptide chain in the present of Cu⁺. Drug Y1can’t take a good preventable effect onthe binding of two complexes of Cu⁺-T17and Cu⁺-T₂₄. Y₂can’t stop or relieve effectively theaggregation of Cu⁺-T4, Cu⁺-T17, Cu⁺-T21, Cu⁺-T₂₄and other protein peptide chains. In theliquid phase the minimum of the vertical binding energy ΔEbais Cu⁺-T10, and the maximum isCu+-T2. By comtrast, the ΔEbaof Cu⁺-Y2is3.6kJ/mol larger than Cu⁺-Y₁（-229.4kJ/mol vs.-224.7kJ/mol）.So Y2takes a better regulatory effect than Y1.The deformation energy of T1and T19are the minimum in the gas phase and of T20is the maximum. Deformation of T4, T9and T13are the minimum in the liquid phase and of T16is the maximum. The distinctivedeformation occurred in gas-liquid phases indicating that solvent effects have a certaininfluence on the deformation of the peptide chain. The deformation of peptide chain inducedby the binding of metal ion reflects the biological activity chnages of the peptide chain.The minimum of the adiabatic binding energy ΔEbaof Cu²⁺-T（Y） in the gas phase lies inCu²⁺-T4while the maximum belongs to Cu²⁺-T15. Y2has an obvious regulatory effect on theaggregation of Cu²⁺-T21and Cu²⁺-T3, and Y1has not. Cu2+-Y1and Cu²⁺-Y₂have small ΔEbadifference （4.4kJ/mol）, thus the regulatory effect of Y1and Y2is consistent. In the liquid phase, Cu⁺-T3has the minimum ΔEba, and Cu⁺-T18has the maximum. The ΔEbaof two drugmolecules have small defference （6.1kJ/mol） in energy, but Y2has better regulatory effectonthe aggregation of Cu2+-T14and Cu²⁺-T2. The deformation energy of Y1and Y2is theminimum and of T9is the maximum in the gas phase. T19will take place minimumdeformation and T16will deform obviously in the liquid phase.In gas-liquid phase the binding energy and charge distribution of Cu⁺-T（Y） and Cu2+-T（Y） are different, showing that in the process of Cu+-T（Y）�'Cu2+-T（Y）+e-, electron transferplays an important role in the protein binding, and affect the drug regulation capacityIn gas phase, the ΔEbaof Zn²⁺-T6is the minimum among) all these Zn²⁺-T（Y） complexes,while that of Zn2+-T3is the maximum. The ΔEbaof Zn²⁺-Y1and Zn²⁺-Y₂are-335.5kJ/moland-328.9kJ/mol, respectively, with a difference of6.63kJ/mol. Thus both Y1and Y₂basically play similar role in regulating the peptide chain aggregation. By contrast, Y1is betterthan Y2.Binding energy changes of peptide chain in gas-liquid twophase indicatethat thesolvent effect is obviously.Comparing with Cu²⁺-T, Y1takes better regulatory effect than Y₂for these Zn²⁺-Tcomplexes in gas phase generally.Both Y1and Y2hardly regulate Zn²⁺-T15、Zn²⁺-T13andZn²⁺-T3among these Zn²⁺-T complexes and Cu²⁺-T13and Cu²⁺-T14among the Cu2+-Tcomplexes. In liquid phase, Y1and Y2do not take regulatory effect for Zn2+-T1、Zn2+-T13、Zn²⁺-T3and Zn²⁺-T17among these Zn²⁺-T complexes, and for Cu2+-T24and Cu2+-T18among Cu²⁺-T complexes.Results show that the stability order of13kinds of cytosine Cnin gas phase can beobtained reliably by employing the HF/CC-PVTZ and SCS-MP2//CC-PVTZ methods. Inliquid phase the most stable isomer of cytosine is C1. Four calculation methods reportsconsistent stability order of CnNa⁺and CnK⁺in liquid phase. The most stable complex is CnM+except for M=K. For the later, C4K⁺is the most stable among these CnK⁺isomers at theSCS-MP2//CC-PVTZ level. The solvent effect takes great effect on the the stability of thesemetal complexes. In gas-liquid phase, four different calculational methods also argue that themost stable complexes for CnCa²⁺and CnMg²⁺are C1M²⁺. The stability order for thesecomplexes changes due to the different calculational methods employed and solvent effects.