研究背景与意义
蛋白质是一种非常重要的生物大分子，是生命活动的物质基础和生物体内一切功能的执行者。一方面，蛋白质或多肽（分子量较小的蛋白质）的自组装（self-assembly）在生物纳米材料设计方面具有重要应用。另一方面，固有无序蛋白（intrinsically disordered proteins，IDPs）或包含低复杂度结构域（low-complexity domain，LCD）的蛋白质在多价相互作用的驱动下发生液-液相分离（liquid-liquid phase separation，LLPS）并形成液态凝集体（liquid condensates）。然而，在突变、翻译后修饰或环境的剧烈改变等作用下，相分离会发生异常，原本可逆的液态凝集体进一步发生病理性的淀粉样聚集（amyloid aggregation），从液相向固相转变，形成不可逆的淀粉样纤维（amyloid fibril）。这些纤维状聚集体所形成的淀粉样斑块或沉积，对细胞具有特定毒性，扰乱细胞的正常功能并导致细胞受损或死亡，最终引起人类疾病的发生，包括阿尔兹海默症、肌萎缩侧索硬化症（渐冻人症）、额颞叶失智症等等。这些与蛋白质相分离和病理性聚集相关并以淀粉样纤维沉淀为主要病理特征的疾病，统称为淀粉样变性病，而其中聚集形成淀粉样纤维而致病的蛋白质称为淀粉样蛋白。此外，蛋白质的相分离和聚集过程会受到环境因素的调控，例如温度、pH、盐离子类型/浓度、生物膜、小分子化合物与纳米颗粒等等。
生物大分子的液-液相分离是一个新兴的研究领域，是当前国际上的研究前沿与热点，涉及重要的生理和病理过程，具有重要的生物学意义。对蛋白质或多肽的相分离、聚集和自组装问题的研究，不仅对从原子分子层次深入理解蛋白质聚集和自组装的微观机制有重要意义，还对淀粉样聚集相关疾病治疗药物的设计和研发具有潜在应用价值。
研究方向
利用分子动力学模拟结合全原子/粗粒化蛋白质模型，研究：
（1）蛋白质的液-液相分离与淀粉样聚集的微观机制；
（2）环境因素（温度、pH、生物膜、天然小分子等）调控蛋白质相分离与聚集的分子机理；
（3）界面诱导的短肽自组装；
（4）固有无序蛋白的构象分布。
已发表论文
（*通讯作者，#具有共同贡献作者）
1. Xianshi Liu, Zenghui Lao, Xuhua Li, Xuewei Dong* and Guanghong Wei*. ALS-associated A315E and A315pT variants exhibit distinct mechanisms in inducing irreversible aggregation of TDP-43312-317 peptide. Physical Chemistry Chemical Physics, 2022, 24(26): 16263-16273. (IF=3.945/JCR-Q2)
2. Xuewei Dong, Santu Bera, Qin Qiao, Yiming Tang, Zenghui Lao, Yin Luo, Ehud Gazit* and Guanghong Wei*. Liquid-liquid phase separation of Tau protein is encoded at the monomeric level. Journal of Physical Chemistry Letters, 2021, 12(10): 2576-2586. (Selected into the Liquid-Liquid Phase Separation virtual collection of ACS, IF=6.888/JCR-Q1)
3. Yujie Chen, Xuhua Li, Chendi Zhan, Zenghui Lao, Fangying Li, Xuewei Dong* and Guanghong Wei*. A comprehensive insight into the mechanisms of dopamine in disrupting Aβ protofibrils and inhibiting Aβ aggregation. ACS Chemical Neuroscience, 2021, 12(21): 4007-4019. (Selected as cover article, IF=5.78/JCR-Q2)
4. Xuewei Dong, Ruxi Qi, Qin Qiao, Xuhua Li, Fangying Li, Jiaqian Wan, Qingwen Zhang and Guanghong Wei*. Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations. Physical Chemistry Chemical Physics, 2021, 23(36): 20406-20418. (IF=3.945/JCR-Q2)
5. Xuewei Dong*,#, Yiming Tang#, Chendi Zhan and Guanghong Wei*. Green tea extract EGCG plays a dual role in Aβ42 protofibril disruption and membrane protection: a molecular dynamic study. Chemistry and Physics of Lipids, 2021, 234: 105024. (IF=3.57/JCR-Q2)
6. Xuewei Dong, Qin Qiao*, Zhenyu Qian and Guanghong Wei*. Recent computational studies of membrane interaction and disruption of human islet amyloid polypeptide: Monomers, oligomers and protofibrils. Biochimica et Biophysica Acta-Biomembranes, 2018, 1860(9): 1826-1839. (IF=4.019/JCR-Q2)
7. Xuewei Dong, Yunxiang Sun, Guanghong Wei*, Ruth Nussinov and Buyong Ma*. Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning. Physical Chemistry Chemical Physics, 2017, 19(40): 27556-27569. (IF=3.945/JCR-Q2)
8. Zenghui Lao, Xuewei Dong, Xianshi Liu, Fangying Li, Yujie Chen, Yiming Tang and Guanghong Wei*. Insights into the atomistic mechanisms of phosphorylation in disrupting liquid-liquid phase separation and aggregation of FUS low-complexity domain. Journal of Chemical Information and Modeling, 2022, 62(13): 3227–3238. (IF=6.162/JCR-Q1)
9. Le Li, Xuewei Dong, Yiming Tang, Zenghui Lao, Xuhua Li and Guanghong Wei*. Deciphering the mechanisms of HPV E6 mutations in the destabilization of E6/E6AP/p53 complex. Biophysical Journal,2022, 121(9): 1704-1714.(IF=3.699/JCR-Q2)
10. Yawei Yu, Xuewei Dong, Yiming Tang, Le Li and Guanghong Wei*. Mechanistic insight into the destabilization of p53TD tetramer by cancer-related R337H mutation: a molecular dynamic study. Physical Chemistry Chemical Physics, 2022, 24(8): 5199-5210. (IF=3.945/JCR-Q2)
11. Santu Bera, Xuewei Dong, Bankala Krishnarjuna, Shannon A Raab, David A Hales, Wei Ji, Yiming Tang, Linda JW Shimon, Ayyalusamy Ramamoorthy, David E Clemmer, Guanghong Wei and Ehud Gazit*. Solid-state packing dictates the unexpected solubility of aromatic peptides. Cell Reports Physical Science,2021, 2(4): 100391. (IF=7.832/JCR-Q1)
12. Xuhua Li, Xuewei Dong, Guanghong Wei*, Martin Margittai, Ruth Nussinov and Buyong Ma*. The distinct structural preferences of Tau protein repeat domains. Chemical Communications, 2018, 54(45): 5700-5703. (IF=6.065/JCR-Q1)
13. Fangying Li, Chendi Zhan, Xuewei Dong and Guanghong Wei*. Molecular mechanisms of resveratrol and EGCG in inhibition of Aβ42 aggregation and disruption of Aβ42 protofibril: similarities and difference. Physical Chemistry Chemical Physics, 2021, 23(34): 18843-18854. (IF=3.945/JCR-Q2)
14. Xuhua Li, Zenghui Lao, Yu Zou, Xuewei Dong, Le Li and Guanghong Wei*. Mechanistic insights into the co-aggregation of Aβ and hIAPP: an all-atom molecular dynamic study. Journal of Physical Chemistry B, 2021, 125(8): 2050-2060. (IF=3.466/JCR-Q3)
15. Jiaqian Wan, Yehong Gong, Zhengdong Xu, Xuewei Dong, Guanghong Wei* and Qingwen Zhang*. Molecular dynamics simulations reveal the destabilization mechanism of Alzheimer's disease-related Tau R3-R4 Protofilament by norepinephrine. Biophysical Chemistry, 2021, 271: 106541. (IF=3.628/JCR-Q3)
16. Yiming Tang, Santu Bera, Yifei Yao, Jiyuan Zeng, Zenghui Lao, Xuewei Dong, Ehud Gazit* and Guanghong Wei*. Prediction and characterization of liquid-liquid phase separation of minimalistic peptides. Cell Reports Physical Science, 2021, 2(9): 100579. (IF=7.832/JCR-Q1)
17. Fangying Li, Yujie Chen*, Xianshi Liu, Yiming Tang, Xuewei Dong and Guanghong Wei*. Atomistic insights into A315E mutation-enhanced pathogenicity of TDP-43 core fibrils. ACS Chemical Neuroscience, 2022, 13(18): 2743-2754. (IF=5.78/JCR-Q2)
18. Duo Gao, Jiaqian Wan, Yu Zou, Yehong Gong, Xuewei Dong, Zhengdong Xu, Jiaxing Tang, Guanghong Wei* and Qingwen Zhang*. The destructive mechanism of Aβ1-42 protofibrils by norepinephrine revealed via molecular dynamics simulations. Physical Chemistry Chemical Physics, 2022, 24(33): 19827-19836. (IF=3.945/JCR-Q2)