从高分子构象与动力学到蛋白质折叠

针对作用在聚合物刷上的键拉力研究表明作用在接枝基面上的力随着聚合物刷接枝密度的增大反而减小,然而尾端单体上的拉伸张力并没有消失.高分子的构象和动力学转变决定了其物性和多种多样的应用,而生物大分子蛋白质作为由二十种不同属性的氨基酸构成的序列,更是具有由其序列所决定的特别的三维自然结构.本文就聚合物刷、聚合物纳米复合材料、聚合物网络等几种高分子体系的构象与动力学过程,及蛋白质构象和其折叠与去折叠的动力学过程做了介绍.特别是蛋白质的折叠与去折叠速率在单分子操纵实验中受到拉力的调控,通过测量这种拉力依赖的动力学过程、蛋白质的自由能曲面和折叠去折叠路径可以得到系统全面的研究.本文以肌肉蛋白titin的免疫球蛋白结构域I27为例对蛋白质折叠研究进行了阐述.     

蛋白质折叠研究的热点

蛋白质折叠、结构和设计国际研讨会(International Workshop on Protein Folding，Structure and Design)于2001年6月11—22日在意大利Drieste，Abdus Salam国际理论物理中心(ICTP)召开．这次会议集中了当今蛋白质折叠研究的大多数知名学者，他们的工作比较全面地代表了目前国际上蛋白质折叠问题研究的前沿．这次会议大多数报告是关于蛋白质模型和它们的折叠机理．会议比较全面地反映了目前国际上蛋白质折叠问题研究的状况，以及未来蛋白质折叠研究发展的方向．目前蛋白质折叠的研究热点有两个方面：一是蛋白质模型的研究．这方面集中在简单的格点模型，主要内容有3个方面：(1)水分子影响．(2)侧链的影响．(3)拓扑结构研究．二是蛋白质折叠机理的研究，主要内容有：(1)热力学性质分析．(2)动力学过程的研究．(3)折叠初期研究．     

蛋白质折叠过程模型

蛋白质折叠过程模型研究一直是蛋白质折叠研究领域的热点课题．就这个问题,提出描述蛋白质折叠过程的拟蛇模型．并且提出一个新的概念,那就是所有蛋白质空间结构都可以通过2种类型函数构造出来,此外,还从理论方面来证明该模型是可行和正确的：通过与其他蛋白质折叠过程模型的对比实验,结果表明,拟蛇模型所构造的空间结构能量值最小、相似度最好．进而说明拟蛇模型在描述蛋白质折叠过程方面具有明显优势,开辟了研究蛋白质的一种新的途径．     

试论蛋白质折叠与生命现象的复杂性

扼要介绍了复杂性科学的哲学涵义；探讨了蛋白质折叠过程与生命的复杂性；并讨论了如何应用复杂性科学指导生命科学的研究。     

基于遗传算法的蛋白质折叠模拟系统

在模拟蛋白质折叠的遗传算法基础上，采用晶格模型，设计了一个用于蛋白质折叠模拟的软件系统，并举例说明该系统的用法。该蛋白质折叠模拟系统可用于蛋白质折叠预测和蛋白质进化研究，并可为蛋白质分子设计提供重要信息。     

蛋白质折叠理论与包涵体的处理

多肽链折叠成天然构象的蛋白质决定于蛋白质的一级结构,另外还需要分子伴侣等蛋白质的协助以及ATP提供能量。大肠杆菌等表达体系表达外源基因时,其表达产物量形成包涵体,利用蛋白质折叠理论,可以分析其产生的原因以及建立恰当的蛋白质复性体系。     

统计物理和蛋白质折叠讲义

本书是作者根据其在清华大学周培源应用数学中心的系列讲座汇编而成。在各种蛋白质数据库中，已经有丰富的蛋白质结构的信息，有一个一致的观点就是：蛋白质折叠主要是由疏水效应造成的，但是还缺乏控制折叠过程的专门的物理原理的理解，此书从统计物理的观点讨论这个问题。     

蛋白质折叠的计算机模拟

介绍了计算机模拟蛋白质折叠问题的背景、模型和意义。在对模型问题采用Ｍｏｎｔｅ－Ｃａｒｌｏ方法和单纯遗传算法得到能量最小构象的基础上,提出了适用的混合遗传算法,并通过计算机模拟试验对三种方法作了比较。     

遗传信息从核酸到蛋白质构象的传输效率

从密码学的观点研究了遗传信息从核酸流各氨基酸和从蛋白质一级结构流向三级结构的信息传输问题，引入了信息传输效率的概念，其对数负正丝 系统的抗干扰能力。导出了信息传输效率与序列长度的关系。发现了信息从核酸流向氨基酸（第一遗传密码）的传输效率和从氨基酸序列流向蛋白质三级结构（第二遗传密码）的传输效率大体相等，这说明了遗传信息的传输效率和抗干扰能力在以上两步传输过程中的匹配性。     

Mixed search algorithm for protein folding

0　IntroductionThedeterminationofthefoldingpathwayfollowedbyaproteinintheconformationalspacefromthedenaturedstatetothenativestructureisstillanunsolvedproblem .Itsdifficultyismainlyduetotheenormousextensionoftheconformationalspaceandtoitsexponentialgrowthwhenthelengthoftheproteinchainincreases.HowaproteinsolvestheLevinthalparadox[1 ] ,i.e.,howitfoldstoitsnativestructurewithoutanexhaustivesearchintheconforma tionalspace,hasbeenlargelydebatedinRef.[2 5 ].Thenatureofthedrivingforcesinducingtheco…     

求解蛋白质折叠问题的改进PERM算法

在学习PERM算法的基础上，指出了影响PERM算法效率的关键因素，进而提出了一种改进的PERM算法——IPERM(Improved PERM)．计算结果表明，IPERM的计算效率优于PERM算法，并且远高于基于蒙特卡罗的MSOE算法和基于重要性抽样的SISPER算法．     

蛋白质折迭时标和分子伴侣的一个简单模型

利用大分子构象动力学导出蛋白质折迭的时标，讨论了折迭时间和分子参量的依赖，着重研究了对构象变化中原子团转动惯量的依赖，在此基础上提出了分子伴侣的一个简单模型。     

Efficient and reproducible folding simulations of the Trp-cage protein with multiscale molecular dynamics

Folding simulations are often time-consuming or highly sensitive to the initial conformation of the simulation even for mini protein like the Trp-cage. Here, we present a multiscale molecular dynamics method which appears to be both efficient and insensitive to the starting conformation based on the testing results from the Trp-cage protein. In this method the simulated system is simultaneously mod- eled on atoms and coarse-grained particles with incremental coarsening levels. The dynamics of coarse-grained particles are adapted to the recent trajectories of finer-grained particles instead of fixed and parameterized energy functions as used in previous coarse-grained models. In addition, the compositions of coarse-grained particles are allowed to be updated automatically based on the coherence during its history. Starting from the fully extended conformation and other several different conformations of the Trp-cage protein, our method successfully finds out the native-like conformations of the Trp-cage protein in the largest cluster of the trajectories in all of the eight performed simulations within at most 10 ns simulation time. The results show that approaches based on multiscale modeling are promising for ab initio protein structure prediction.     

Respective roles of short-and long-range interactions in protein folding

A new method was presented to discuss the respective roles of short- and long-range interactions in protein folding. It‘s based on an off-lattice model, which is also being called as toy model. Simulated annealing algorithm was used to search its native conformation. When it is applied to analysis proteins lagt and laho, we find that helical segment catmot fold into native conformation without the influence of long-range interactions. That‘s to say that long-range interactions are the main determinants in protein folding.     

Determination of free energy of protein folding on liquid-solid interface

Based on the fact that the stoichiometric displacement model for retention of solute and the total adsorption free energy of solute on a solid surface can be divided into two components, net adsorption and net desorbed energies, a new principle and an equation for calculating the free energy of protein folding, △△GF, on the solid surface are proposed. With high-performance hydrophobic interaction chromatography (HPHIC), an experimental method for determining the △△GF is established. Lysozyme and α-amylase have been selected as examples to test the new method, and their △△GF on the HPHIC stationary phase surface are found to be much higher than that reported from a solution. In addition, the △△GF of the two proteins are found to increase with the concentration of denaturing agent employed. The average standard deviations, ±4.7% for lysozyme and ±3.0% for α-amylase, indicate that the new method has a satisfactory reproducibility and reliability.     

蛋白质微秒级折叠过程的快速模拟

使用ff12SB力场和广义玻恩(GB Neck2)隐性水模型在GTX670 GPU上对4个蛋白质CLN025 (2ZEI)、MHA6(2I9M)、Trp Cage (1L2Y)、Villin (3TRW)的微秒级折叠过程进行了分子动力学模拟,2ZEI的折叠时间和均方根偏差为5.94 μs和0.897 ,2I9M的折叠时间和均方根偏差为0.191 μs和1.142 ,Villin的折叠时间和均方根偏差为4.23 μs和1.37 ,Trp Cage的折叠时间和均方根偏差为2.48 μs和0.63 。结果表明,蛋白质折叠模拟已经能够通过GPU计算在桌面计算机上实现。     

Personification algorithm for protein folding problem：Improvements in PERM

PERM is the most efficient approach for solving protein folding problem based on simple lattice model. In this article a personification explanation of PERM is proposed. A new version of PERM, population control algorithm with two main improvements is presented: one is that it is able to redefine the weight and its predicted value in PERM,and the other is that it is able to unify the calculation of weight when choosing possible branches. The improved PERM is more efficient than the previous version; specifically it can find the known lowest energy states for the four well-known difficult instances and is generally several to hundreds times faster than PERM. It is noteworthy that with the improved PERM we found new lowest energy configurations of three of the four difficult problems missed in previous papers.