Computer Simulations for Folding/Unfolding of Peptides and Large-scale Functional Motions of Proteins

摘要

蛋白质折叠—去折叠和大尺度的功能运动是结构生物学中两个非常重要的研究方向.除了一系列实验技术(例如X射线、核磁共振等等)以外,计算机模拟对于研究这些问题具有不可替代的作用,它能够给出皮秒(10<'-12>秒)到微秒(10'<-6>秒)时间尺度内蛋白质原子水平上的动力学信息.生物大分子的计算机模拟这个领域开展时间并不算很长,但是已经在研究蛋白质折叠—去折叠和功能运动等方面取得了很大的成功,并且还在进一步的发展完善之中.该文使用了两个体系对ACM方法做了检验.首先,我们将ACM与一种溶剂化模型generalizedBorn/surfacearea(GB/SA)相结合,较快地实现了S肽类似物变性α-helix的复性;而通常的GB/SA模拟由于采样效率的问题未观察到复性.另一个体系是噬菌体T4溶菌酶(T4L),我们研究了溶菌酶N端结构域和C端结构域之间的运动.在水溶液中的模拟结果表明,ACM模拟在3纳秒时间内,采样效率比3纳秒常规分子动力学模拟要高,两个结构域之间的运动"放大"了,而且与实验结果符合得很好.上述结果表明ACM方法在研究蛋白质的折叠-去折叠、大尺度功能运动以及结构预测等方面有良好的应用前景.

目录

文摘

英文文摘

Acknowledgement

Chapter 1. Introduction

1.1. Protein folding/unfolding

1.1.1. Definitions of protein folding/unfolding

1.1.2. Driving forces and thermodynamics of protein folding/unfolding

1.1.3. Folding scenarios and mechanisms

1.2. Large-scale functional motions of proteins

1.3. From experiments to theory

1.4. Computer simulation techniques: Applications in biomotecutes

1.4.1. Molecular dynamics simulation

1.4.2. Protein dynamics in collective coordinate space

1.4.3. Sampling techniques based on collective coordinates

1.4.4. Stochastic path approach to long time dynamics of proteins

1.5. Outline of this thesis

Chapter 2. Molecular dynamics simulations of urea and thermal-induced denaturation of a S-peptide analog

Abstract

2.1. Introduction

2.2. Materials and methods

2.2.1. Molecular dynamics simulations

2.2.2. Contact analysis

2.2.3. Cluster analysis

2.2.4. Essential dynamics analysis

2.3. Results and discussion

2.3.1. Native structure

2.3.2. Global behavior

2.3.3. Mode of action of urea

2.3.4. Comparison between urea and thermal-induced denaturation

2.4. Conclusion

Acknowledgments

Chapter 3. Molecular dynamics simulations of peptides and proteins with amplified collective motions

Abstract

3.1. Introduction

3.2. Theory and methods

3.2.1. Gaussian network model and the anisotropic network model

3.2.2. Amplified-collective-motions method

3.3. Computational details

3.3.1. S-peptide analog

3.3.2. Bacteriophage T4 lysozyme

3.4. Results and discussion

3.4.1. Folding/unfolding of S-peptide analog

3.4.2. Domain motions in bacteriophage T4 lysozyme

3.4.3. Comparisons with other sampling methods

3.5. Conclusions

Acknowledgments

Chapter 4. Concluding remarks

4.1. Current state of the art

4.2. Limitations

4.3. Outlook

Reference list

List of publications