聚酰胺-胺树枝形大分子导致<italic style="font-style: italic">α</italic>-突触核蛋白聚集动力学变缓

秦超然; 黄瑞静; 宋祥燕; 田文得

doi:10.11777/j.issn1000-3304.2022.22180

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聚酰胺-胺树枝形大分子导致α-突触核蛋白聚集动力学变缓

研究论文 | 更新时间：2023-05-22

- 聚酰胺-胺树枝形大分子导致α-突触核蛋白聚集动力学变缓
  增强出版
- The Aggregation Dynamics of α-Synucleins Slowed Down by Polyamindoamine
- 高分子学报 2023年54卷第1期页码：87-94
- 作者机构：
  
  苏州大学软凝聚态物理及交叉研究中心物理科学与技术学院苏州 215000
- 作者简介：
  
  E-mail: tianwende@suda.edu.cn
- 基金信息：
  
  想：国家自然科学基金(基金号21474074)
- DOI：10.11777/j.issn1000-3304.2022.22180
  中图分类号：
- 纸质出版日期：2023-01-20，
  
  网络出版日期：2022-09-19，
  
  收稿日期：2022-06-06，
  
  录用日期：2022-06-27
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秦超然,黄瑞静,宋祥燕等.聚酰胺-胺树枝形大分子导致α-突触核蛋白聚集动力学变缓[J].高分子学报,2023,54(01):87-94.

Qin Chao-ran,Huang Rui-jing,Song Xiang-yan,et al.The Aggregation Dynamics of α-Synucleins Slowed Down by Polyamindoamine[J].ACTA POLYMERICA SINICA,2023,54(01):87-94.
秦超然,黄瑞静,宋祥燕等.聚酰胺-胺树枝形大分子导致α-突触核蛋白聚集动力学变缓[J].高分子学报,2023,54(01):87-94. DOI： 10.11777/j.issn1000-3304.2022.22180.

Qin Chao-ran,Huang Rui-jing,Song Xiang-yan,et al.The Aggregation Dynamics of α-Synucleins Slowed Down by Polyamindoamine[J].ACTA POLYMERICA SINICA,2023,54(01):87-94. DOI： 10.11777/j.issn1000-3304.2022.22180.

摘要

采用基于Martini力场的粗粒化分子动力学模拟研究了聚酰胺-胺(PAMAM)树枝形大分子对

-突触核蛋白NAC区域聚集行为的影响，发现PAMAM树枝形分子的存在延缓了NAC区域聚集过程，增长了聚集体形成的时间. 团簇形成的主要时间段里，大小与时间满足一定标度关系(~

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663717&type=

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663715&type=

3.47133350

3.13266683

且存在PAMAM时，标度指数

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663719&type=

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663718&type=

1.26999998

2.96333337

减小. PAMAM大分子的代数和浓度越高，聚集体形成时间就越长；研究结果支持实验提出的“动力学抑制”猜想.

Abstract

Inhibition of fibril assembly is a potential therapeutic strategy in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The NAC

a fragment of

-synuclein

is considered to be the key region of

α‍

-synuclein that causes Parkinson's disease. It has been recently shown that the polyamidoamine (PAMAM) dendrimer is promising candidate for the treatment of Parkinson's diseases. However

it is still not very clear that how and why the PAMAM could inhibit the protein aggegration. In this study

the interaction between PAMAM dendrimers and NAC fragments was investigated by molecular dynamics simulation.The coarse-grained Martini field was adopted for PAMAM and proteins and the effects of generation and concentration of PAMAM dendrimers on the aggregation dynamics were studied. We mainly built nine systems and G3-G5 PAMAM dendrimers were used. The systems for

-synucleins of 10.4 mmol/L were built without PAMAM

and with 0.80 and 1.04 mmol/L PAMAM dendrimers

respectively. All systems are simulated with a long time of 5000 ns. In the Martini force field

the real time is about 20 μs. It was found that the addition of PAMAM molecules could slow down the aggregation process and increase the formation time of the largest cluster. The larger the dendrimer generation and the higher concentration

the larger the degree of inhibition of the NAC aggregation. Taking the existence of 5 clusters in the box as the criterion

the aggregation time is about 180 ns for the system without PAMAM dendrimers

~230 ns for the system with five G3-PAMAM dendrimers

~400 ns for the system with five G4-PAMAM dendrimers

~400 ns for the system with three G5-PAMAM dendrimers

and ~500 ns for the system with five G5-PAMAM dendrimers. Meanwhile

there exists a scaling relation between cluster size

and simulation time

with

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663739&type=

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663738&type=

2.20133328

2.79399991

. When adding PAMAM

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663728&type=

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663740&type=

1.43933344

3.21733332

=0.54

which is smaller than that without PAMAM

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663732&type=

http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=43663730&type=

1.43933344

3.21733332

=0.69. In addition

in our parameter spaces

the disaggeration of the existing NAC cluster was observed when dendrimers were added in the system. Our results are in good agreement with experimental findings and support the hypothesis of kinetic inhibition

in which case

the final amount of aggegrates remained unchanged with the varying lag time.

关键词

分子动力学模拟聚酰胺-胺树枝形分子蛋白质聚集

Keywords

Molecular dynamics simulationPolyamindoamine dendrimerProtein aggregation

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The Aggregation Dynamics of α-Synucleins Slowed Down by Polyamindoamine

DOI：10.11777/j.issn1000-3304.2022.22180

摘要

Abstract

关键词

Keywords

references