基于联合残基模型的蛋白折叠模拟
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摘要
蛋白质结构预测和蛋白质折叠机制的研究是相当有挑战性并且吸引人的研究方向。尽管在过去的几十年里面，蛋白质折叠研究已经取得了相当大的进步，但是，直至现在，蛋白折叠的研究里仍有相当多未能完全解决的问题。本论文主要是采用一种用以研究蛋白质折叠的简化模型——联合残基模型(UNRES)来研究蛋白质的折叠路径，并在研究折叠路径的同时来改进我们所使用的联合残基模型。我们的工作有助于对蛋白质折叠机制的进一步认识和联合残基模型的改进。具体的讲，我们做了以下几个方面的工作：
1)采用联合残基模型对Trptophan Zipper 2(Trpzip2)蛋白的折叠路径进行了研究。我们发现对Trpzip2这样一个由12个氨基酸组成的小肽段，它从直链结构(非天然态)折叠到天然结构有两种折叠机制：拉链模式和拉链—疏水塌缩同时发生的模式，而每种路径是以一定概率出现的。拉链模式发生的概率约为72％，这也说明了为什么实验上观察到的都是拉链模式，因为实验上总是观测到出现概率最大的事件。另外，我们发现Trpzip2的折叠过程可能是二态的过程，也可能是三态的过程。我们的研究有助于理清目前β发卡折叠机制中存在的矛盾。
2)采用联合残基模型研究了较大蛋白的折叠过程。我们选取了长度为120个氨基酸的6螺旋蛋白1Q2Z，模拟了48条长为110纳秒的1Q2Z折叠的独立分子动力学轨道，并且所有这些模拟轨道均从直链开始。这个蛋白成功折叠到它的天然结构并且整个折叠过程可以用以下几步来描述。首先是迅速地在局部形成二级结构同时伴以疏水塌缩，然后各个局域螺旋片段之间开始聚合在一起，最后再把各个聚合体拼装成正确的三级结构。我们同时发现这个蛋白的前半段(前三个螺旋)和后半段(后三个螺旋)能独立折叠到它们的天然结构。我们还发现如果把这个6螺旋蛋白切成三段，每个片段都有一定独立折叠的能力。这说明这个蛋白很可能是由更小的蛋白或多肽片段进化而来的。
3)将1Q2Z蛋白切成不同长度的片段，并采用联合残基模型对这些片段进行了独立的动力学模拟。从我们的模拟中可以看出，三个螺旋组成的片段的稳定性好于两个螺旋组成的片段。从我们序列比对的结果中也可以看出，1Q2Z具有两对称性。所以，我们有理由推断1Q2Z可能是有两个三螺旋结构单元组成的。并且，在这些1Q2Z片段折叠的过程中，这些片段展现出了与1Q2Z蛋白相似的折叠过程。
4)研究了联合残基模型可能的权重参数空间的范围。因为一些新的能量项参数和温度依赖性的加入使得联合残基模型拥有更高的精度和可靠性，但是同时使得我们必须要重新确定联合残基力场各项的权重参数。因此，必须有一个用以力场优化的初始点。为了这个目标，我们随机在力场权重构成的参数空间里取了一百个初始点，并采用了分层次的筛选机制来得到理想的初始点。一个包含13个测试蛋白的测试集用来测试随机产生的初始点的折叠能力。利用我们筛选出的力场权重集，大部分测试集里的蛋白可以产生类天然结构。而且，从我们的结果可以看出，随机搜索力场参数空间是可行的，并且我们设计的分层次的筛选法则也是有效的，它可以用于力场参数的粗选。同时，我们建议进行更大规模的筛选以获得更好的初始点
Study protein folding and protein folding mechanisms is a very difficult but also attractive task. In the past decades, protein folding research has achieved lots of successes, but there are still many problems need to be solved. My research is focused on studying protein folding mechanisms with United-Residue (UNRES) model and improving UNRES force field. Our research can help people understanding both small peptides and real proteins folding mechanisms. We also did some researches about UNRES force field. More detiales about my research are listed as following:
1) We employed UNRES to study a short peptide: Trptophan Zipper 2(Trpzip2) folding mechanisms. We find that this small peptide folds from extended structure to native structure following two folding mechanisms: zipper and simultaneously zipper & hydrophobic collapse. Each folding mechanism appears with different probabilty. The "Zipper" mechanism appears with a probabilty around 72%, this may explain why only "zipper" mechanism observed in the experimental research, since the experimental research always oberved the most probable events. We also find that the folding process of trpzip2 is not only a two states process but also a three states process. Our results may help to clarify the inconsistencies in the current picture of the folding mechanisms ofβhairpins.
2) In the following, we extended the application of UNRES to real protein. We employed UNRES approach to study folding processes of a Six-helix protein domain (the C-terminal domain of Ku86 protein, PDB ID: 1Q2Z). We simulated 48 110-ns independent molecular dynamics trajectories with UNRES starting from extended conformations of this protein. This protein successfully folds into its native state and the results show that its folding process is relatively simple: firstly the secondary structures form very fast with the hydrophobic collapse, then helix pairs form and finally these pairs assemble into the tertiary structure. We also find the first-half (the first three helices) and last-half (the last three helices) parts of this protein can fold into their native conformations independently and this suggests that this protein may be evolved from smaller polypeptides or proteins.
3) We cut six helix-bundle protein (PDB ID:1Q2Z) into slices by different ways. Then a series of molecular dynamics simulations with these slices were carried out by UNRES. The results shows that the slices containing three helices are more stable than the slices containing two helices. As shown in our sequence alignment results, the first half of 1Q2Z has sequence similarity to the second half. So we have reason to suppose that 1Q2Z may consist of two parts/fragments. Besides, all these slices show the same folding behaves as the whole 1Q2Z protein.
4) We also did something on UNRES force field. UNRES force field is more and more elaborate, lots of energy term parameters have been changed, so this new UNRES force field needs to be reparameterized. Based on Prof. Liwo's unpublished work, we knew the parameter space of UNRES. We introduced a method which can be used to decide initial parameter sets for UNRES optimization. Recently, temperature-dependence and new energy term parameters have been applied to UNRES in order to develop a more powerful and reliable force field and thus the UNRES force field parameters (weight of energy terms) must be reparameterized. Therefore, a good initial parameter set for UNRES force field optimization will be needed. With this goal, we randomly generated parameter sets in the parameter space and applied a hierarchical selection procedure to obtain appropriate initial parameter sets for UNRES force field optimization. A training set which contains 13 proteins was used to test the folding ability of these parameter sets. The results show that most proteins in our training set reach native-like structures with the parameter sets selected by our procedure. Our results suggest that it is possible to randomly search the force field parameter space to find good initial parameter sets and our procedure could be used for gross selection of good initial parameter sets for UNRES force field optimization. We also suggest that it is possible to find a better force field directly though further extensively searching of UNRES parameter space.
This work is supported by the National Natural Science Foundation of China under Grant No.30525037 and No.30470412.
1)采用联合残基模型对Trptophan Zipper 2(Trpzip2)蛋白的折叠路径进行了研究。我们发现对Trpzip2这样一个由12个氨基酸组成的小肽段，它从直链结构(非天然态)折叠到天然结构有两种折叠机制：拉链模式和拉链—疏水塌缩同时发生的模式，而每种路径是以一定概率出现的。拉链模式发生的概率约为72％，这也说明了为什么实验上观察到的都是拉链模式，因为实验上总是观测到出现概率最大的事件。另外，我们发现Trpzip2的折叠过程可能是二态的过程，也可能是三态的过程。我们的研究有助于理清目前β发卡折叠机制中存在的矛盾。
2)采用联合残基模型研究了较大蛋白的折叠过程。我们选取了长度为120个氨基酸的6螺旋蛋白1Q2Z，模拟了48条长为110纳秒的1Q2Z折叠的独立分子动力学轨道，并且所有这些模拟轨道均从直链开始。这个蛋白成功折叠到它的天然结构并且整个折叠过程可以用以下几步来描述。首先是迅速地在局部形成二级结构同时伴以疏水塌缩，然后各个局域螺旋片段之间开始聚合在一起，最后再把各个聚合体拼装成正确的三级结构。我们同时发现这个蛋白的前半段(前三个螺旋)和后半段(后三个螺旋)能独立折叠到它们的天然结构。我们还发现如果把这个6螺旋蛋白切成三段，每个片段都有一定独立折叠的能力。这说明这个蛋白很可能是由更小的蛋白或多肽片段进化而来的。
3)将1Q2Z蛋白切成不同长度的片段，并采用联合残基模型对这些片段进行了独立的动力学模拟。从我们的模拟中可以看出，三个螺旋组成的片段的稳定性好于两个螺旋组成的片段。从我们序列比对的结果中也可以看出，1Q2Z具有两对称性。所以，我们有理由推断1Q2Z可能是有两个三螺旋结构单元组成的。并且，在这些1Q2Z片段折叠的过程中，这些片段展现出了与1Q2Z蛋白相似的折叠过程。
4)研究了联合残基模型可能的权重参数空间的范围。因为一些新的能量项参数和温度依赖性的加入使得联合残基模型拥有更高的精度和可靠性，但是同时使得我们必须要重新确定联合残基力场各项的权重参数。因此，必须有一个用以力场优化的初始点。为了这个目标，我们随机在力场权重构成的参数空间里取了一百个初始点，并采用了分层次的筛选机制来得到理想的初始点。一个包含13个测试蛋白的测试集用来测试随机产生的初始点的折叠能力。利用我们筛选出的力场权重集，大部分测试集里的蛋白可以产生类天然结构。而且，从我们的结果可以看出，随机搜索力场参数空间是可行的，并且我们设计的分层次的筛选法则也是有效的，它可以用于力场参数的粗选。同时，我们建议进行更大规模的筛选以获得更好的初始点
Study protein folding and protein folding mechanisms is a very difficult but also attractive task. In the past decades, protein folding research has achieved lots of successes, but there are still many problems need to be solved. My research is focused on studying protein folding mechanisms with United-Residue (UNRES) model and improving UNRES force field. Our research can help people understanding both small peptides and real proteins folding mechanisms. We also did some researches about UNRES force field. More detiales about my research are listed as following:
1) We employed UNRES to study a short peptide: Trptophan Zipper 2(Trpzip2) folding mechanisms. We find that this small peptide folds from extended structure to native structure following two folding mechanisms: zipper and simultaneously zipper & hydrophobic collapse. Each folding mechanism appears with different probabilty. The "Zipper" mechanism appears with a probabilty around 72%, this may explain why only "zipper" mechanism observed in the experimental research, since the experimental research always oberved the most probable events. We also find that the folding process of trpzip2 is not only a two states process but also a three states process. Our results may help to clarify the inconsistencies in the current picture of the folding mechanisms ofβhairpins.
2) In the following, we extended the application of UNRES to real protein. We employed UNRES approach to study folding processes of a Six-helix protein domain (the C-terminal domain of Ku86 protein, PDB ID: 1Q2Z). We simulated 48 110-ns independent molecular dynamics trajectories with UNRES starting from extended conformations of this protein. This protein successfully folds into its native state and the results show that its folding process is relatively simple: firstly the secondary structures form very fast with the hydrophobic collapse, then helix pairs form and finally these pairs assemble into the tertiary structure. We also find the first-half (the first three helices) and last-half (the last three helices) parts of this protein can fold into their native conformations independently and this suggests that this protein may be evolved from smaller polypeptides or proteins.
3) We cut six helix-bundle protein (PDB ID:1Q2Z) into slices by different ways. Then a series of molecular dynamics simulations with these slices were carried out by UNRES. The results shows that the slices containing three helices are more stable than the slices containing two helices. As shown in our sequence alignment results, the first half of 1Q2Z has sequence similarity to the second half. So we have reason to suppose that 1Q2Z may consist of two parts/fragments. Besides, all these slices show the same folding behaves as the whole 1Q2Z protein.
4) We also did something on UNRES force field. UNRES force field is more and more elaborate, lots of energy term parameters have been changed, so this new UNRES force field needs to be reparameterized. Based on Prof. Liwo's unpublished work, we knew the parameter space of UNRES. We introduced a method which can be used to decide initial parameter sets for UNRES optimization. Recently, temperature-dependence and new energy term parameters have been applied to UNRES in order to develop a more powerful and reliable force field and thus the UNRES force field parameters (weight of energy terms) must be reparameterized. Therefore, a good initial parameter set for UNRES force field optimization will be needed. With this goal, we randomly generated parameter sets in the parameter space and applied a hierarchical selection procedure to obtain appropriate initial parameter sets for UNRES force field optimization. A training set which contains 13 proteins was used to test the folding ability of these parameter sets. The results show that most proteins in our training set reach native-like structures with the parameter sets selected by our procedure. Our results suggest that it is possible to randomly search the force field parameter space to find good initial parameter sets and our procedure could be used for gross selection of good initial parameter sets for UNRES force field optimization. We also suggest that it is possible to find a better force field directly though further extensively searching of UNRES parameter space.
This work is supported by the National Natural Science Foundation of China under Grant No.30525037 and No.30470412.
引文
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