用于真实蛋白质结构预测的一种新的优化方法

用“相对熵”作为优化函数 ,提出了一个有效快速的折叠预测优化算法 .使用了非格点模型 ,预测只关心蛋白质主链的走向 .其中只用到了蛋白质主链上的两两连续的Cα 原子间的距离信息以及 2 0种氨基酸的接触势的一个扩展形式 .对几个真实蛋白质做了算法测试 ,预测的初始结构都为比较大的去折叠态 ,预测构象相对于它们天然结构的均方根偏差 (RMSD)为 5～ 7 .从原理上讲 ,该方法是对能量优化的改进 .     

非天然氨基酸在蛋白质动态特性核磁共振研究中的应用

核磁共振（NMR）是蛋白质结构解析的主要方法之一.除可获得蛋白质的高分辨结构外,NMR还可用于观测最接近生理条件的蛋白质动态构象,获得蛋白质行使生物学功能的详细机制.非天然氨基酸定点标记方法可显著减少大分子量蛋白质的信号数目,降低数据采集和分析难度,已广泛运用于蛋白质结构和功能研究.本文介绍了常用的在蛋白质中引入非天然氨基酸的实验方法,包括蛋白质化学合成法、蛋白质化学修饰法、氟代芳香族氨基酸插入和基因密码子编辑的位点特异性插入等方法,并介绍了部分应用非天然氨基酸结合NMR研究大分子量蛋白的成功案例.此外,此篇综述讨论了目前非天然氨基酸标记在蛋白质研究中的局限性及发展方向.     

EPR和NMR自旋标记法研究部分折叠蛋白质构象

部分折叠蛋白质的特征是在溶液中有部分二级结构,但是三级结构接触比较松散或者较少,其意义可能是蛋白质折叠过程的中间态,或者有重要的生理功能. 利用EPR和NMR波谱可以表征其构象特征,从而构建其二级结构、三级结构、四级结构以及构象变化的结构模型. 利用分子生物学的点突变技术可以在蛋白质主链上插入1个或2个半胱氨酸残基,然后把顺磁自旋标记物特异地共价结合在半胱氨酸的侧链巯基上来制备自旋标记样品. 位点特异性自旋标记电子顺磁共振（SDSL-EPR）波谱是通过测定2个自旋标记间的偶极相互作用,从而推测2个硝基氧自由基间的距离. 核磁共振（NMR）波谱则是通过测定单个自旋标记中心对周围原子核驰豫效应增强（PRE）的效应,推测出顺磁中心相对于周围原子核的距离. 连续波EPR和NMR自旋标记方法可以测定2.5 nm左右的偶极相互作用距离,属于长程的距离约束,这对于确定部分折叠蛋白质的构象至关重要. 该文将就蛋白质部分折叠态研究的生物学意义,自旋标记方法以及EPR和NMR方法研究其构象特征举例描述.     

蛋白质结构预测

从氨基酸序列出发预测蛋白质的三维结构是目前计算生物学和生物物理学领域最具挑战性和影响力的研究方向之一.本文从结构预测的研究背景出发,简要介绍了它的理论意义、应用需求及基本现状;并根据结构预测的一般步骤,依次介绍了构象初始化、构象搜索、结构筛选、全原子结构重建、结构优化等基本预测过程;随后分基于模板和无模板两类,各列举了几种具有代表性的结构预测方法;最后对该领域的盛事——国际蛋白质结构预测技术评估大赛(CASP)做了简单介绍.     

基于改进确定采样型滤波的疲劳裂纹扩展预测

针对确定性采样滤波在进行状态估计预测时随维数增加时出现计算量增加且精度不高的问题,提出一种确定采样型滤波的算法并将其应用到疲劳裂纹扩展预测当中去。首先,阐述了确定采样型滤波器的基本原理;其次,从多维数值积分的角度出发,引入完全对称积分公式,根据不变容积法则选取容积节点作为基础采样点,计算积分节点、节点个数和权重;最后,将改进后的确定采样型滤波器应用到构件疲劳裂纹损伤扩展中去,并与无迹卡尔曼滤波算法、容积卡尔曼滤波算法进行比较,提升了裂纹扩展预测的精度,仿真分析验证了该方法的可行性和有效性。     

基于禁忌搜索的车联网蒙特卡洛定位算法

在蒙特卡洛定位算法中引入禁忌搜索算法以提高车联网中快速定位的性能。自组织车联网高速移动的车辆和快速变化的网络拓扑结构,使用传统的蒙特卡洛定位算法,不能迅速的收敛位置信息。在滤波阶段引入禁忌搜索算法对传统蒙特卡洛定位算法进行改进, 优化滤波排除可能性较小的位置点,获得近似最优估计位置采样集。仿真结果表明,改进后的算法在样本采集数、计算时间、定位精度等方面有了显著提升,改进后的算法能更好地解决车联网的定位问题。     

增强采样分子动力学模拟在生物分子研究中的进展

分子动力学模拟能够描述蛋白质分子在行使生物学功能过程中涉及的构象变化,已发展成为中物学研究中重要的计算工具.由于生物分子的构象分布存在崎岖的自由能面,在较为复杂的生物体系的模拟中,传统的分子动力学模拟的构象采样能力受到极大限制,模拟的时间尺度与真实的生物学过程之间仍存在差距.增强采样是解决这一问题的有效手段.本文综述了两类增强采样方法即约束型和无约束型增强采样算法的理论基础、最新进展及其在生物分子中的典型应用,同时也简要总结了组合型增强采样算法近些年的发展.     

增强采样分子动力学模拟在生物分子研究中的进展（英文）

分子动力学模拟能够描述蛋白质分子在行使生物学功能过程中涉及的构象变化,已发展成为中物学研究中重要的计算工具.由于生物分子的构象分布存在崎岖的自由能面,在较为复杂的生物体系的模拟中,传统的分子动力学模拟的构象采样能力受到极大限制,模拟的时间尺度与真实的生物学过程之间仍存在差距.增强采样是解决这一问题的有效手段.本文综述了两类增强采样方法即约束型和无约束型增强采样算法的理论基础、最新进展及其在生物分子中的典型应用,同时也简要总结了组合型增强采样算法近些年的发展.     

基于改进Faster R-CNN的红外目标检测算法

为提升红外目标的检测精度,提出了一种引入频域注意力机制的Faster R-CNN红外目标检测算法。首先,针对红外图像边缘模糊和噪声问题,设计了一种并行的图像增强预处理结构;其次,在Faster R-CNN中引入频域注意力机制,设计了一种新型红外目标检测主干网络;最后,引入路径增强金字塔结构,融合多尺度特征进行预测,利用底层网络丰富的位置信息,提升检测精度。在红外飞机的数据集上进行实验,结果表明,改进后的Faster R-CNN目标检测框架比以ResNet50为主干的算法的AP提升了7.6%。此外,与目前主流算法对比,本文算法提高了红外目标的检测精度,验证了算法改进的有效性。     

两种微生物源谷氨酰胺转氨酶与底物特异性识别的全原子动力学模拟研究

微生物源谷氨酰胺转氨酶(Transglutaminase, TGase)能够催化蛋白间氨酰基转移促进蛋白交联,已经广泛应用于食品、轻工等多种领域.然而目前微生物源TGase与底物间基于长程作用力的分子特异性识别机制仍不清楚,理性改造困难.本研究以源自高茂源链霉菌(MTG)和源自枯草芽孢杆菌(BTG)的两种TGase为研究对象,使用分子对接技术构建酶与底物的结合复合体并使用分子动力学模拟解析两种TGase与底物识别的分子机制.结果显示两种TGase在底物识别过程高度类似,均由催化腔外周loop区域氨基酸残基通过范德华及静电作用固定底物整体,而后由位于催化腔底部催化三联体内Asp(MTG)或Glu(BTG)通过羧基侧链稳定反应发生局部空间构象并拉近底物Gln内γ-酰胺基与核心催化残基Cys间距,以便后续反应过程中TGase-底物中间体的生成.上述结果阐明了TGase与底物活性基团的分子识别模式,提出了两种TGase内作用于底物识别的氨基酸残基,为以后TGase的理性改造研究提供了理论基础.     

Sources of and solutions to problems in the refinement of protein NMR structures against torsion angle potentials of mean force

It is often the case that a substantial number of torsion angles (both backbone and sidechain) in structures of proteins and nucleic acids determined by NMR are found in physically unlikely and energetically unfavorable conformations. We have previously proposed a database-derived potential of mean force comprising one-, two-, three-, and four-dimensional potential surfaces which describe the likelihood of various torsion angle combinations to bias conformational sampling during simulated annealing refinement toward those regions that are populated in very high resolution (< or =1.75 A) crystal structures. We now note a shortcoming of our original implementation of this approach: namely, the forces it places on atoms are very rough. When the density of experimental restraints is low, this roughness can both hinder convergence to commonly populated regions of torsion angle space and reduce overall conformational sampling. In this paper we describe a modification that completely eliminates these problems by replacing the original potential surfaces by a sum of multidimensional Gaussian functions. Structures refined with the new Gaussian implementation now simultaneously enjoy excellent global sampling and excellent local choices of torsion angles.     

Conformational studies of poly(methacrylic acid). I. Conformational energy calculations on lsotactic and syndiotactic poly(methacrylic acid)

The conformational energies of isotactic and syndiotactic poly (methacrytic acid) were calculated for isolated chains in order to determine the most probable helical conformations. It was concluded that the most probable backbone conformation of the isotactic polymer is either a 5₂ or 8₃ helix, where the internal rotations of the two helices are nearly equal. The left-handed and right-handed conformations were also essentially equienergy conformations. Two lowenergy helical conformations were found for the syndiotactic polymer. One of these conformations had backbone internal rotations nearly identical to those of the 5₂ and 8₃ helices of isotactic poly(methacry1ic acid). The second conformation was a nearly planar structure containing two monomer units in the axial repeat unit, with backbone rotation angles nearly identical to those of the 5₂ and 8₃ helices or their negatives.

Deformation of the backbone C─C─C bond angles was considered in the conformational energy calculations. The optimum bond angles for both isotactic and syndiotactic polymer chains were considerably larger than the normal tetrahedral bond angle. The relative energies calculated for helical conformations were influenced by the backbone bond angles. It was demonstrated that the failure to consider backbone bond-angle deformation may lead to erroneous conformational assignments in disubstituted vinyl polymers.     

DNA condensation and size effects of DNA condensation agent

Based on the model of the strong correlation of counterions condensed on DNA molecule, by tailoring interaction potential, interduplex spacing and correlation spacing between condensed counterions on DNA molecule and interduplex spacing fluctuation strength, toroidal configuration, rod-like configuration and two-hole configurations are possible. The size effects of counterion structure on the toroidal structure can be detected by this model. The autocorrelation function of the tangent vectors is found as an effective way to detect the structure of toroidal conformations and the generic pathway of the process of DNA condensation. The generic pathway of all of the configurations involves an initial nucleation loop, and the next part of the DNA chain is folded on the top of the initial nucleation loop with different manners, in agreement with the recent experimental results.     

CORCEMA refinement of the bound ligand conformation within the protein binding pocket in reversibly forming weak complexes using STD-NMR intensities

We describe an intensity-restrained optimization procedure for refining approximate structures of ligands within the protein binding pockets using STD-NMR intensity data on reversibly forming weak complexes. In this approach, the global minimum for the bound-ligand conformation is obtained by a hybrid structure refinement method involving CORCEMA calculation of intensities and simulated annealing optimization of torsion angles of the bound ligand using STD-NMR intensities as experimental constraints and the NOE R-factor as the pseudo-energy function to be minimized. This method is illustrated using simulated STD data sets for typical carbohydrate and peptide ligands. Our procedure also allows for the optimization of side chain torsion angles of protein residues within the binding pocket. This procedure is useful in refining and improving initial models based on crystallography or computer docking or other algorithms to generate models for the bound ligand (e.g., a lead compound) within the protein binding pocket compatible with solution STD-NMR data. This method may facilitate structure-based drug design efforts.     

基于多算法优化SVM的粗糙面参数反演

支持向量机（SVM）是粗糙面参数反演中常用的一种反演算法,SVM反演中的惩罚参数C和核函数参数G对反演结果精度的影响较大,若参数取值不当,会使模型产生"过学习"或者"欠学习"的现象,从而降低预测精度.给出几种SVM参数C和参数G的优化算法,如K折交叉验证（K-CV）、遗传算法（GA）和粒子群算法（PSO）,并在此基础上提出一种基于K-CV和GA改进的PSO算法（GA-CV-PSO）.利用矩量法（MoM）获得的粗糙面后向散射系数构造训练集和测试集,通过不同参数反演的仿真结果对比不同优化算法的反演精度和计算时间,表明GA-CV-PSO算法克服了单一优化算法的缺陷,具有更精确的反演精度和更强的泛化能力.     

Random walks in the space of conformations of toy proteins

Monte Carlo dynamics of the lattice toy protein of 48 monomers is interpreted as a random walk in an abstract (discrete) space of conformations. To test the geometry of this space, we examine the return probability P(T), which is the probability to find the polymer in the native state after T Monte Carlo steps, provided that it starts from the native state at the initial moment. Comparing computational data with the theoretical expressions for P(T) for random walks in a variety of different spaces, we show that conformation spaces of polymer loops may have nontrivial dimensions and exhibit negative curvature characteristics of Lobachevskii (hyperbolic) geometry.     

New algorithms to look for the most stable conformations of a molecule

Summary Some new algorithms useful for the study of the ≪low-energy conformational space≫ of a molecule are described, and in particular an algorithm which detects the most stable conformations through a random sampling of the energy hypersurface. An application of this algorithm to ethylmethylphosphate (a model molecule of the chain segment of nucleic acids between two furanose rings) is also shown. Presented in part at the Fourth Annual Montedison Chemistry Meeting (Milan, March 4, 1986).     

On the conformation and the structure of polymacromonomers

Using poly( -norbornenyl polystyrene) as a model we studied the conformation and the structure of branched polymer chains each of whose backbone constitutive units bear a branch. The parameters taken into account are: the polymerisation degree of the backbone, the molar mass of the branches and the solution concentration. The effect of the global conformation of these polymacromonomers, either spherically or cylindrically (vermiform) symmetric, is considered. The compactness of the polymer constitutive unit distribution, the branches and the backbone conformations are considered as functions of the first two parameters above. Significant results are obtained on all of these three points.Received: 24 May 2004, Published online: 21 September 2004PACS: 61.12.Ex Neutron scattering - 61.41. + e Polymers, elastomers, and plastics - 61.46. + w Nanoscale materials: clusters, nanoparticles, nanotubes, and nanocrystals     

Conformation-dependent sequence design: evolutionary approach

A new modification of evolutionary approach to sequence design of copolymers has been proposed. A model of step-by-step evolution of a two-letter (HP) copolymer sequence has been studied by means of a coarse-grained Monte Carlo algorithm. The conditions for accepting a change in the primary sequence depend on the spatial conformation of HP-copolymer chain. This leads to a coupling between sequence and conformation and to formation of protein-like conformations and primary sequences (for some values of parameters of the model) independently of initial sequence and/or conformation. Simple theory describing these computer simulation observations is developed.Received: 3 September 2003, Published online: 2 March 2004PACS: 87.15.Aa Theory and modeling; computer simulation - 87.15.Cc Folding and sequence analysis - 82.35.Jk Copolymers, phase transitions, structure - 82.35.Lr Physical properties of polymers