【作者】 陈进；

【导师】 章林溪；

【作者基本信息】 浙江大学 ， 凝聚态物理， 2006， 博士

【摘要】 研究赋予生物功能的自然构象以及形成这些构象的机理与力学性质是十分重要的,因为它是了解生物体的基础。在这个基础上,人们才能根据分子序列中包含的丰富信息对其结构进行正确的预测,寻找到结构和功能之间的联系。本文主要对蛋白质分子、DNA分子和紧密高分子的构象与序列进行理论分析和模拟计算,通过对这些大分子的折叠构象性质与力学性质的研究,有助于加深对生物大分子结构的认识。第二章中,采用粗粒化模型,研究了不同蛋白质分子中20种氨基酸形成远程和近程紧密接触对的能力。发现疏水性氨基酸容易形成远程紧密接触对,反之亲水性氨基酸不易形成远程紧密接触对；而对近程紧密接触对来说,它的形成能力不会根据氨基酸残基亲疏水性的改变而改变,更大程度上依赖于蛋白质的一维序列,即氨基酸的排列顺序,而不是蛋白质的三维结构,因此在研究蛋白质的折叠过程及其稳定性时,远程紧密接触对有着更加重要的意义。此外,用氨基酸重心替代ca碳原子的方法研究了(α／β)8桶状蛋白质,同样也发现了疏水性氨基酸对远程紧密接触对形成的重要贡献。还采用简化的二维HP紧密高分子链模型研究其在折叠过程中的构象变化。采用精确计数法,计算紧密高分子链在折叠的不同阶段其尺寸大小及分布情况。最后研究了428种球状蛋白质形成紧密接触对的统计规律,并进行蛋白质二级结构的预测。发现不同折叠类型的蛋白质有着不同的紧密接触对的形成能力,全α型蛋白质比较容易形成近程紧密接触对,而β型的更容易形成远程紧密接触对,α／β和α+β型性质比较接近。我们可以据此了解蛋白质的球状结构情况,判断不同的折叠类型,也可以证明a螺旋和β折叠在形成蛋白质稳定结构中的重要作用。这些研究工作为我们认识蛋白质结构,解决蛋白质的折叠过程提供了一条新的途径。随着核酸序列数据爆炸式的增长和互联网的发展,为我们提供了丰富的资源信息,使我们可以从这些现有的大量DNA数据中发掘出那些隐藏着的对于基因组进化机制有用的信息。因此在第三章中,采用DNA行走的方法讨论了DNA序列中远程相关性和几何拓扑性质,通过计算参量均方距离<R2(l)>、位移变化的均方根F(l)和自相关函数C(l)分别得到<R2(l)>-lr,F(l)-lHr和C(l)-l-μ这样的标度关系,证实DNA序列中存在着几何分形这样的物理事实。此外,还研究了DNA序列中CG团簇的标度行为与编码和非编码序列的关系,通过分析分布函数P(S)和ζ(m),发现它们具有很好的标度行为P(s)∝e-as和ξ(m)∝m-r,通过讨论指数α和γ可以很简便地区分出编码序列和非编码序列。同时还发现编码序列的性质更加接近于随机序列,说明非编码序列中包含着更加丰富的生物信息,这些为深入研究DNA分子中的序列信息提供了理论依据。第四章中,采用Monte Carlo方法和键长涨落模型分析了在拉伸过程中吸附高分子链的构象变化,发现强吸附作用对弹性过程的重要影响。此外,紧密高分子作为蛋白质分子的简化模型,通过内部紧密接触对的相互作用,可以形成空间上的紧密结构。简化后的模型不仅能粗略体现蛋白质分子的统计性质,而且这种模型也可以更加方便地运用于计算机模拟之中。因此,我们采用完全计算法研究了二维紧密高分子模型中紧密接触对的形成速率。发现形成速率与链长之间可以近似满足K(N)∝N-α,其中指数α不仅与紧密接触对半径α、序列类型有关,还与所选用的紧密接触对能量数值相关。通过与完全计算法和PERM算法的结合,计算了链的形状因子<δ>,回转张量半径S,均方回转半径<S2>,均方末端距<R2>等,讨论了在不同吸附空间下(如单一吸附面、平行板吸附面和无限长吸附通道)紧密高分子链的构象性质。希望这些粗略模型的研究能够加深我们对受限吸附紧密高分子链性质的了解。最后采用同样的模型和方法研究了在拉伸过程中吸附紧密高分子链的力学行为,讨论了理论研究的特点,发现模拟结果与实验结论比较类似。这些工作有助于我们了解生物大分子的结构情况,解释生命活动机理,从而了解生物体本身。更多还原

【Abstract】 It’s important to investigate the native conformation, folding mechanism and thermodynamic properties of biomacromolecules. The relation between the structure and the function can be found in biomacromolecular sequences. In this dissertation, we investigate the conformation properties, the elastic behavior of biomacromolecules and long-range correlation of DNA sequences in order to help us to understand the organism clearly.In Chapter 2, we use coarse-grained model to calculate statistical properties of residue-residue contacts based on a large number of proteins from PDB. By analyzing the effects of amino acid residues on long-and short-range contacts, we can get the conclusion that hydrophobic residues are easy to form long-range contacts, while hydrophilic residues are difficult. However short-range contacts only depend on residue sequence. Long-range contacts play an active role in protein folding and the stability of proteins. We also discuss the statistical properties of residues for (α/β)8 barrel proteins using a new model in which Ca is replaced by the center position, and find that the average residue contacts per residue in all residue pairs is good to differentiate the interior and the exterior residues. At the same time, a simple two-dimensional HP compact lattice model is used to investigate the conformation change during folding process. We find that the size of compact chains is small at the beginning of folding process, and the size distribution depends on residue sequence. Statistical properties of long-and short-contacts based on 428 globular proteins are also studied. Proteins with different secondary structures have different ability of forming contacts. All-a proteins are easy to form short-range contacts while all-βproteins are easy to form long-range contacts. Andα/βproteins are similar toα+βproteins. This investigation can provide a new path to understand the properties of protein structure and folding mechanism.With the development of computer technique, we can dig out hidden and available information in DNA sequences. So in Chapter 3, the long-range correlation in DNA sequences using two-dimensional DNA walk are firstly discussed. The mean-square distance, root-mean-square fluctuation and autocorrelation function are obey the power law< R2(l)>-lr, F(l)-lHr and C(l)-l-μrespectively. On the other hand, the statistical properties of CG clusters in coding and non-coding DNA sequences are investigated through calculating the cluster-size distribution of CG clusters P(S) and the breadth of the distribution of the root-mean-square size of CG clustersξ(m) in consecutive, non-overlapping blocks of m bases, and we also find the relation of P(s)∝e-as andξ(m)∝m-r. There exist some differences between coding and non-coding sequences by analyzing the exponents a and y, and the behavior of coding sequences is more similar to random sequences. These results can provide some insights into the long-range correlations of DNA sequences.In Chapter 4, the elastic behavior of single polymer chains adsorbed on the attractive surface is calculated by Metropolis Monte Carlo simulation method and the bond fluctuation model. And compact polymer chains can form stable structures by intra-molecular contacts, which can represent the native conformation of proteins well. So we first consider the rate of intra-molecular contact formation in short two-dimensional compact polymers. The rate of contact formation decreases with the number of bonds, and approximately conforms to the scaling relation of K(N)∝N-α, where the value ofαincreases with the contact radius a and also depends on the percentage of hydrophobic residues in different sequences. We also calculate some statistical properties, such as mean-square end-to-end distance< R2>, mean-square radii of gyration <S2> and shape factor<δ> in order to illuminate how the size and shape of adsorbed compact chains change during the process of tensile elongation.Thermodynamic properties are also studied in Chapter 5. Different elastic behaviors are obtained for adsorbed compact polymer chains. Elastic force has a long plateau during the tensile elongation for strong adsorption interaction, which agrees well with experimental and theoretical results. These calculations can help us to understand the elastic behavior of compact polymer chains and find out the relation between the structure and the function.更多还原