Theoretical Study Of Copper And Zinc Ions With A¦Â Peptide Bonding Mode

Alzheimer's disease(AD),also known as Senile dementia sickness.It is a primary degenerative encephalopathy occurred in early old age and old age.It is a persistent obstacle to high-level neurological function.It is barriers of memory,thinking,analysis,identification of visual spatial, emotional in the absence of state of consciousness.One of the main pathological features of AD patients is the senile plaques.The main component of senile plaques(SP) isβ-amyloid peptide(Aβ).The research indicates that coprecipitation of theβ-amyloid peptide gradually gathered fibrosis in AD patients brain and other related proteins,polyose formed brain senile plaques.Senile plaques have nerve toxicity,and its expansion will lead to neuronal atrophy,necrosis.Many metal ions such as Cu²⁺,Fe³⁺,Ca²⁺,Zn²⁺,Al³⁺ play an important role in the body's physiological and metabolic processes,including nerve cell metabolism.Its metabolic abnormalities may lead to various diseases. Alzheimer's disease induced by these metal ions through it in the deposition of Aβpeptide and the formation of SP.The molecular mechanism of copper,zinc ions caused aggregation of Aβpeptide is generally considered that metal ions and Aβpeptide formed cross-linking betweenβ-pleated sheets.And a number of experiments also showed that the deposition of Aβpeptide is caused through the metal ions,especially abnormal copper,zinc ion caused chelation.In this paper,we used the methods of quantum mechanics and molecular mechanics combined (QM/MM).The work of this paper is to use ONIOM method of Gaussian03 package.The system will be divided into two sections for study the system.Part of the active site using DFT methods,and the rest part the use of a molecular mechanics approach.We studied the mechanism of transition metal ions in the Alzheimer's disease with QM/MM method.In this paper,the research include: The QM/MM studies for soluble bonding mode of copper ions with Aβpeptide,The theoretical research of bond model of Aβpeptide and the zinc ions.The main contents and conclusions of the study are lised as follows:1.To N atoms of the Aβpeptide histidine imidazole ring as main bonded site,in the ONIOM (B3LYP:UFF) level,Studied the soluble bond model of copper ion and Aβpeptide.The structures, stabilities,and vibration frequencies of Coordination Compounds of the copper ions and 3N1O, 2N2O,3O1N ligand of Aβpeptide were investigated.The results shows that:The structure of copper ion and NÏ„atom of AβPolypeptide chain histidine imidazole ring formed compounds than the structure with NÏ€atom formed compounds more stable,which is shows that the most important bonding site is histidine imidazole ring NÏ„atoms of Aβpeptide with the copper ions bonded. 2.Bonded mode of Aβpeptide and zinc ions.The legend is N atoms of His6,His13,His14 and O atoms on the side chain.Mainly we were studied zinc ions with single-chain Aβpeptides may be formed with four compounds and bonding mode of zinc ions with multi-chains Aβpeptide.Optimize, stability and vibration frequency of compound structures in the ONIOM(B3LYP:UFF) level.The results showed that:The major complexation sites of metal ion are Histidine and Tyrosine residues of Aβpeptides;in the aggregation of Aβ,the His13(NÏ„)-Zn²⁺-His14(NÏ„) bridges are formed by Zn²⁺ cross-linking action.So it leading to inter-peptide cross-linking and aggregation.