Thr231磷酸化对顺式和反式tau蛋白226-236多肽六聚体结构的影响  

Phosphorylation of Thr231 slightly differentiates the structure and interactions of cisand trans-tau226-236 peptide hexamers

作　　者：孟青青 曾鑫成 苏玉红 白钢钢 Ruth Nussinov 马步勇 MENG Qing-qing;ZENG Xin-cheng;SU Yu-hong;BAI Gang-gang;Ruth Nussinov;and MA Bu-yong(Engineering Research Center of Cell&Therapeutic Antibody(MOE),School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240,China)

机构地区：[1]上海交通大学药学院,细胞工程及抗体药物教育部工程研究中心,上海200240 [2]Basic Science Program,Leidos Biomedical Research,Inc.,Frederick National Laboratory for Cancer Research,National Cancer Institute at Frederick,Frederick,MD 21702,USA [3]Sackler Inst.of Molecular Medicine Department of Human Genetics and Molecular Medicine Sackler School of Medicine,Tel Aviv University,Tel Aviv 69978,Israel

出　　处：《阿尔茨海默病及相关病杂志》2020年第4期258-266,共9页Chinese Journal of Alzheimer's Disease and Related Disorders

基　　金：上海交通大学启动资金资助RN由美国癌症研究所项目HHSN261200800001E资助。

摘　　要：目的:研究Thr231磷酸化对于顺-反式tau异构体构象以及聚集行为的影响,探讨可能的在阿尔茨海默病和相关疾病中的毒性关联。方法:采用副本交换分子动力学模拟分析Tau蛋白226-246多肽片段六聚体的相互作用和结构。采用NAMD和CHARMM36分子力场的隐式溶剂化GBIS模型。使用了温度分布从300K到450K的56个模拟副本,每个模拟副本的模拟时间为200 ns,总模拟时间为11200 ns。结果:天然态时Thr231-Pro232是顺式和反式Tau226-236六聚体的相互作用中心,尽管顺式和反式tau多肽六聚体中肽链间有着不同的主链相互作用。反式比顺式tau多肽更易形成主链间氢键,226VAVVR231T部分在顺反式tau中均有4-10%的²结构,而反式tau多肽²结构略多。虽然反式tau蛋白多肽比顺式更为伸展末端距较长,但顺式和反式Tau226-236六聚体具有类似的表面积和回转半径。Thr231磷酸化完全破坏了顺式tau中主链间的氢键和²结构,反式Tau226-236六聚体中主链间的氢键和²结构也随Thr231磷酸化而减少,但影响较小。磷酸化Thr231在顺-反式Tau226-236六聚体中都易与Arg230形成盐桥。Thr231磷酸化促使顺式Tau226-236六聚体中VAVV部分有较大的疏水暴露面积,而这一作用在反式Tau226-236六聚体中较小。结论:Thr231磷酸化对顺式和反式Tau226-236六聚体结构有不同的影响,但是缺乏清晰的局部结构区别。Thr231磷酸化后六聚体中VAVV部分疏水暴露面积的差异和顺反式Tau226-236末端距的明显差别需要在全长Tau蛋白单体和寡聚体中进一步研究。Objective:Investigate the effects of pT231 on the structure and peptide interaction in cis-and trans-tau oligomers,to examine their possible toxic mechanisms in Alzheimer’s disease.Methods:Using replica-exchange molecular dynamics simulations,we studied the cis-and trans-hexamers of Tau225-246fragment.The 56 replicas were simulated using NAMD program and CHARMM36 force field with GB model,from 300K to 450 K.Each replica was simulated for 200 ns,with total 11200 ns simulation time.Results:Interestingly,the backbone hydrogen bonds involving T231P232 have higher frequencies,indicated that they are the local interaction hot spots even before T231 phosphorylation.The backbone hydrogen bonds are more populous in trans-than in cis-tau hexamer.The 226VAVVR231T fragment has about 4-10%bstructure,more in trans-than in cis-hexamer.Although that the peptide N-to C-terminal distances are longer in trans-tau peptide,the cis-and trans-tau hexamers have similar solvent-accessible-surface areas and radius of gyrations.The Thr231phosphorylation abolished most backbone hydrogen bonds andbstructures in cis-tau hexamer,but has less effects on trans-tau hexamer.The phosphate group forms salt bridge mostly with Arg230 in both cis-and trans-hexamer.However,phosphate prefer to form hydrogen bond with amide hydrogen of Arg230 in cis-hexamer,while in trans-hexamer the phosphate binds more to amide hydrogen of Lys234.The most decisive effects of T231 phosphorylation could be the exposed hydrophobic surface area of VAVV,which increases about 100Å2 after phosphorylation in cis-hexamer.But these areas are similar for trans-hexamer before and after T231 phosphorylation.Conclusion:Thr231 phosphorylation has different effects on the structure and chemical interaction in cisand trans-Tau226-236hexamer.But there is no clear-cut difference that can link the local structure change to the toxicity of the tau oligomer.The differentiate effects of phosphorylation on the hydrophobic surface area of VAVV in cis-and trans-tau hexamer and the longer end-

关 键 词：阿尔茨海默病 TAU蛋白 淀粉样变性 磷酸化 分子动力学模拟 

分 类 号：R741[医药卫生—神经病学与精神病学]