蛋白质折叠和稳定性的全原子模拟研究
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摘要
蛋白质折叠和稳定的机制是生命科学中没有解决的重大科学问题,一直是国际上研究的热点。所谓蛋白质折叠机制,即指蛋白质由一维序列折叠到三维结构的具体过程。了解该机制将加深我们对蛋白质自组装过程的认识,进而为治疗各种蛋白质折叠病(如疯牛病和老年痴呆症)提供帮助,为蛋白质分子设计提供指导。另一方面,天然和设计蛋白质分子三维结构的稳定性是它们实现其功能的基础,因此对蛋白质稳定机制的研究具有重要理论和应用价值。
本论文针对蛋白质折叠和稳定性问题主要做了三方面的工作:
第一,提出了一种提高蛋白质分子模拟采样效率的新方法。目前,蛋白质折叠模拟中的难题之一,是传统的蒙特卡罗和分子动力学等方法采样效率过低,不能有效地模拟蛋白质分子的折叠。目前国际上提出了各种改进算法,其中最著名的是Essential Dynamics Sampling (EDS),Amplified Collective Motion (ACM)和Replica Exchange Method (REM)。我们在EDS和ACM的基础上提出了一种简单有效的新算法:Directed Essential Dynamics (DED)。DED的主要思想是,利用主分量分析法(Principal Component Analysis,PCA)找出分子在每20飞秒间隔内本征值最大(即包含分子运动的信息最多)的六个集合运动模式,然后在这些模式对应的方向上加一个弱力,以加强分子在这些模式中采样。该方法能够大大提高构象空间的采样效率,避免长时间陷入局部最小态。对长度为15个氨基酸的S肽分子模拟结果表明,在DED的帮助下,S肽可以很顺利地折叠到天然态,而传统动力学方法却很难做到这一点。
第二,发现β-发卡trpzip2能够通过不同的折叠机制折叠到天然态。由于蛋白质自由度太大,目前还不能在全原子水平上模拟整个蛋白质的折叠。β-发卡由于具有类似于蛋白结构中的长程作用和疏水核,对理解蛋白质整体的折叠机制非常有帮助,成为研究的焦点之一。对于β-发卡的折叠机制,目前国际上有几种不同的模型,其中最著名的是zip-out和hydrophobic cluster模型。我们利用传统分子动力学方法成功地得到了β-发卡trpzip2的10个折叠事件,发现它可以随着疏水核形成方式不同而采用不同的折叠机制。这说明目前提出的折叠机制并不互相矛盾,可以用一个统一图像来描述。我们同时发现,在发卡的自由能表面上,存在一些比天然态的熵更低的局部稳定态,这是出乎预料的现象。
第三,提出了用全原子相互作用能定义氨基酸接触(contact)。一般认为蛋白质的稳定性与其内部氨基酸接触网络有关。氨基酸接触通常是用氨基酸间距离来定义的。我们认为用相互作用能定义更严格和精确,而且实际应用表明这是正确的。通过分析了15个家族的嗜热和常温蛋白,我们发现接触能和对应的接触数作为特征量比其它方法能更好地区分嗜热和常温蛋白。特别是还发现,除了公认的带电残基接触外,带电-极性和带电-非极性接触也是蛋白质稳定的重要因素。我们还研究了转导素蛋白Gβ结构域中的关键氨基酸,发现关键氨基酸一般都具有较低的接触能,这为预测蛋白质中关键氨基酸提供了一种新的途径。用基于距离定义的氨基酸接触无法定位这些关键氨基酸。
The folding and stability mechanisms of proteins are unsolved key problems in life science and have been a hotspot of researches. The folding mechanism is referred to the process that protein folds from one-dimensional sequence to the 3-dimensional structure. Understanding this mechanism would greatly accelerate our study on the protein self-assembling, and moreover, be helpful to protein design and to the treatment of various diseases relevant to protein misfolding (such as mad cow disease and Alzheimer disease). And the stability of native and designed proteins is the base of protein function. So it is also very significant to study the stability mechanism of proteins.
This thesis includes works of three aspects in protein folding and stability:
First, we proposed a new method of increasing the sampling efficiency of protein simulation. Currently, the sampling efficiency in traditional methods, such as Monte Carlo and molecular dynamics, is the big obstacle to simulate protein folding. Up to now, many novel methods have been put out. The most famous of them are Essential Dynamics Sampling (EDS), Amplified Collective Motion (ACM), and Replica Exchange Method (REM). Based on EDS and ACM, we proposed a new sampling method: Directed Essential Dynamics (DED). The main idea of DED is to use the principal component analysis (PCA) to determine six slowest collective motions of peptide every 20fs during the folding process and then add an additional weak force along the combined direction of this motions to adjust the folding direction. This method can make the peptides avoid trapping in the local minima for long time and enhance the sampling efficiency in conformational space during the simulation. As an application, one S-peptide with 15 amino acids is used to demonstrate the DED method. The results show that DED can lead the S-peptide fold quickly into the native state, while the traditional molecular dynamics needs more times to do this.
Second, we found that theβ-hairpin trpzip2 can fold into its native state through multiple pathways. Due to the large degrees of freedom, it is difficult to simulate the entire folding processes of large proteins. Therefore, smallβ-hairpins become the focus since they have similar long-range interactions and hydrophobic cores in the protein structures and their folding mechanism would be very helpful to understand those of entire proteins. Forβ-hairpin folding mechanisms, different models have been proposed, including the famous zip-out and hydrophobic cluster models. We studied the trpzip2 and obtained 10 successful entire folding trajectories. The results show the trpzip2 could fold into the native state though multiple pathways, depending on the ways of the formation of the hydrophobic core. This means that the previously proposed folding mechanisms are not in paradox and they could be described in a unified way. Furthermore, we find that the native state of the hairpin does not have the lowest entropy and some non-native states exhibit even lower entropies.
Third, we proposed a new method to define inter-residue contact in proteins. Generally, protein stability is thought to be related to its inter-residue contact network. Inter-residue contact is usually defined by the distance between the residues. Our analysis suggests it is more accurate to define the contact with all-atom interaction energy. Our following applications support this. We study fifteen groups of mesophilic and thermophilic proteins and find that the contact energy and contact number are better criterions, comparing with other methods, to distinguish thermophilic proteins from their mesophilic counterparts. Additionally it indicates that the charged-polar and charged-nonpolar contacts are also the key factors for the protein stability, besides the charged-charged contacts. We also apply our method in identifying the key residues in the Gβprotein domain from transducin. We find that most key residues in this protein can be located by the lowest contact energies, but not by distance-defined contacts. This gives a new approach to predict and analyze the key residues in proteins.
本论文针对蛋白质折叠和稳定性问题主要做了三方面的工作:
第一,提出了一种提高蛋白质分子模拟采样效率的新方法。目前,蛋白质折叠模拟中的难题之一,是传统的蒙特卡罗和分子动力学等方法采样效率过低,不能有效地模拟蛋白质分子的折叠。目前国际上提出了各种改进算法,其中最著名的是Essential Dynamics Sampling (EDS),Amplified Collective Motion (ACM)和Replica Exchange Method (REM)。我们在EDS和ACM的基础上提出了一种简单有效的新算法:Directed Essential Dynamics (DED)。DED的主要思想是,利用主分量分析法(Principal Component Analysis,PCA)找出分子在每20飞秒间隔内本征值最大(即包含分子运动的信息最多)的六个集合运动模式,然后在这些模式对应的方向上加一个弱力,以加强分子在这些模式中采样。该方法能够大大提高构象空间的采样效率,避免长时间陷入局部最小态。对长度为15个氨基酸的S肽分子模拟结果表明,在DED的帮助下,S肽可以很顺利地折叠到天然态,而传统动力学方法却很难做到这一点。
第二,发现β-发卡trpzip2能够通过不同的折叠机制折叠到天然态。由于蛋白质自由度太大,目前还不能在全原子水平上模拟整个蛋白质的折叠。β-发卡由于具有类似于蛋白结构中的长程作用和疏水核,对理解蛋白质整体的折叠机制非常有帮助,成为研究的焦点之一。对于β-发卡的折叠机制,目前国际上有几种不同的模型,其中最著名的是zip-out和hydrophobic cluster模型。我们利用传统分子动力学方法成功地得到了β-发卡trpzip2的10个折叠事件,发现它可以随着疏水核形成方式不同而采用不同的折叠机制。这说明目前提出的折叠机制并不互相矛盾,可以用一个统一图像来描述。我们同时发现,在发卡的自由能表面上,存在一些比天然态的熵更低的局部稳定态,这是出乎预料的现象。
第三,提出了用全原子相互作用能定义氨基酸接触(contact)。一般认为蛋白质的稳定性与其内部氨基酸接触网络有关。氨基酸接触通常是用氨基酸间距离来定义的。我们认为用相互作用能定义更严格和精确,而且实际应用表明这是正确的。通过分析了15个家族的嗜热和常温蛋白,我们发现接触能和对应的接触数作为特征量比其它方法能更好地区分嗜热和常温蛋白。特别是还发现,除了公认的带电残基接触外,带电-极性和带电-非极性接触也是蛋白质稳定的重要因素。我们还研究了转导素蛋白Gβ结构域中的关键氨基酸,发现关键氨基酸一般都具有较低的接触能,这为预测蛋白质中关键氨基酸提供了一种新的途径。用基于距离定义的氨基酸接触无法定位这些关键氨基酸。
The folding and stability mechanisms of proteins are unsolved key problems in life science and have been a hotspot of researches. The folding mechanism is referred to the process that protein folds from one-dimensional sequence to the 3-dimensional structure. Understanding this mechanism would greatly accelerate our study on the protein self-assembling, and moreover, be helpful to protein design and to the treatment of various diseases relevant to protein misfolding (such as mad cow disease and Alzheimer disease). And the stability of native and designed proteins is the base of protein function. So it is also very significant to study the stability mechanism of proteins.
This thesis includes works of three aspects in protein folding and stability:
First, we proposed a new method of increasing the sampling efficiency of protein simulation. Currently, the sampling efficiency in traditional methods, such as Monte Carlo and molecular dynamics, is the big obstacle to simulate protein folding. Up to now, many novel methods have been put out. The most famous of them are Essential Dynamics Sampling (EDS), Amplified Collective Motion (ACM), and Replica Exchange Method (REM). Based on EDS and ACM, we proposed a new sampling method: Directed Essential Dynamics (DED). The main idea of DED is to use the principal component analysis (PCA) to determine six slowest collective motions of peptide every 20fs during the folding process and then add an additional weak force along the combined direction of this motions to adjust the folding direction. This method can make the peptides avoid trapping in the local minima for long time and enhance the sampling efficiency in conformational space during the simulation. As an application, one S-peptide with 15 amino acids is used to demonstrate the DED method. The results show that DED can lead the S-peptide fold quickly into the native state, while the traditional molecular dynamics needs more times to do this.
Second, we found that theβ-hairpin trpzip2 can fold into its native state through multiple pathways. Due to the large degrees of freedom, it is difficult to simulate the entire folding processes of large proteins. Therefore, smallβ-hairpins become the focus since they have similar long-range interactions and hydrophobic cores in the protein structures and their folding mechanism would be very helpful to understand those of entire proteins. Forβ-hairpin folding mechanisms, different models have been proposed, including the famous zip-out and hydrophobic cluster models. We studied the trpzip2 and obtained 10 successful entire folding trajectories. The results show the trpzip2 could fold into the native state though multiple pathways, depending on the ways of the formation of the hydrophobic core. This means that the previously proposed folding mechanisms are not in paradox and they could be described in a unified way. Furthermore, we find that the native state of the hairpin does not have the lowest entropy and some non-native states exhibit even lower entropies.
Third, we proposed a new method to define inter-residue contact in proteins. Generally, protein stability is thought to be related to its inter-residue contact network. Inter-residue contact is usually defined by the distance between the residues. Our analysis suggests it is more accurate to define the contact with all-atom interaction energy. Our following applications support this. We study fifteen groups of mesophilic and thermophilic proteins and find that the contact energy and contact number are better criterions, comparing with other methods, to distinguish thermophilic proteins from their mesophilic counterparts. Additionally it indicates that the charged-polar and charged-nonpolar contacts are also the key factors for the protein stability, besides the charged-charged contacts. We also apply our method in identifying the key residues in the Gβprotein domain from transducin. We find that most key residues in this protein can be located by the lowest contact energies, but not by distance-defined contacts. This gives a new approach to predict and analyze the key residues in proteins.
引文
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