邻苯二甲酸酯类塑化剂电子结构特征的理论研究

采用量子化学密度泛函理论和极化连续介质模型在B3LYP/6-311++G**水平上对DEHP、MEHP、DBP、MBP和雌二醇在水溶液中的电子结构特征进行了理论研究,获得了上述化合物的几何构型、表观静电势、前线轨道等信息;采用电子密度拓扑分析方法分析获得了分子中的键鞍点电荷密度. 在此基础上,对分子电子结构与生物活性的关系进行了初步探讨. 结果表明,MBP、MEHP分子表观正、负电势程度比DBP、DEHP大,有利于与受体形成稳定的复合物;MBP、MEHP的ΔEgap分别比DBP、DEHP更小,反应活性更高;MBP、MEHP的分子偶极矩比DBP、DEHP相应提高了22%、34%,有利于与受体分子之间的氢键相互作用、偶极-偶极相互作用. 以上研究结果验证了MBP、MEHP毒性分别高于DBP、DEHP的实验结论. 研究还发现,邻苯二甲酸酯类塑化剂与雌二醇在电子结构特征上存在较大差异,该类化合物可能具有与雌二醇不同的受体或结合位点.     

邻苯二甲酸酯类塑化剂电子结构特征的理论研究

采用量子化学密度泛函理论和极化连续介质模型在B3LYP/6-311++G**水平上对DEHP、MEHP、DBP、MBP和雌二醇在水溶液中的电子结构特征进行了理论研究，获得了上述化合物的几何构型、表观静电势、前线轨道等信息；采用电子密度拓扑分析方法分析获得了分子中的键鞍点电荷密度. 在此基础上，对分子电子结构与生物活性的关系进行了初步探讨. 结果表明，MBP、MEHP分子表观正、负电势程度比DBP、DEHP大，有利于与受体形成稳定的复合物；MBP、MEHP的ΔEgap分别比DBP、DEHP更小，反应活性更高；MBP、MEHP的分子偶极矩比DBP、DEHP相应提高了22%、34%，有利于与受体分子之间的氢键相互作用、偶极-偶极相互作用. 以上研究结果验证了MBP、MEHP毒性分别高于DBP、DEHP的实验结论. 研究还发现，邻苯二甲酸酯类塑化剂与雌二醇在电子结构特征上存在较大差异，该类化合物可能具有与雌二醇不同的受体或结合位点.     

活细胞中的化学物理-光学观测和控制细胞内信号转导（英文）

在活细胞拥挤的微环境中生物大分子之间存在着不间断的物理和化学相互作用.细胞功能直接取决于其内部的分子组成和分子间相互作用.不仅不同种细胞之间的化学和物理性质千差万别,同一细胞内的物理特性也会受环境影响不断产生动态变化.而这种动态变化的化物特性对于细胞适应环境的改变至关重要.通常环境的改变会引起细胞产生不同响应,比如改变其基因的转录和翻译.是否形成正确的细胞响应取决于细胞对外部环境信息的准确解读.而这种解读通常是通过细胞内信号转导途径来实现.一个化学或物理的信号会通过刺激一系列细胞内的生化反应将外部环境的信息准确地传递到细胞内部.由于信号传导过程经常需要穿跨各亚细胞空间的复杂路径,所以细胞内信号转导的实际功用就是一座连接外部环境与细胞内部的桥梁.了解信号分子在细胞微环境中的化物状态将有助于阐释细胞功能.当今实验和理论工具的发展已使得在活细胞这样的微环境中探索纷繁的分子化物性质成为可能.本文总结如何利用新兴的光学显微镜和光遗传技术去观测甚至控制生物信号在细胞内的传导过程.确信这些技术已经为精确控制生物体中分子的化学和物理性质提供了前所未有的机遇.希望本文可以为有兴趣研究生物和医学问题的化学物理研究人员抛砖引玉.     

多纳米粒子穿越磷脂膜（英文）

本文采用耗散粒子动力学模拟方法研究了多纳米粒子与溶液中的磷脂膜相互作用.模拟中选择纳米颗粒的形状分别为球状和柱状,并且在动力学过程中给它们设置了不同的初始速度.根据纳米粒子穿膜在动力学过程中体现出不同的特性,分别定义了几种粒子穿越磷脂的模式,并且基于粒子之间的相互作用强度和粒子初始速度,描绘了穿膜模式的详细相图.本文还进一步研究了体系能量、迴旋半径等参数在不同穿越模式中的动力学过程.研究结果有助于人们理解纳米颗粒穿膜在生命活动过程中的作用.     

多纳米粒子穿越磷脂膜

本文采用耗散粒子动力学模拟方法研究了多纳米粒子与溶液中的磷脂膜相互作用. 模拟中选择纳米颗粒的形状分别为球状和柱状，并且在动力学过程中给它们设置了不同的初始速度. 根据纳米粒子穿膜在动力学过程中体现出不同的特性，分别定义了几种粒子穿越磷脂的模式，并且基于粒子之间的相互作用强度和粒子初始速度，描绘了穿膜模式的详细相图. 本文还进一步研究了体系能量、迴旋半径等参数在不同穿越模式中的动力学过程. 研究结果有助于人们理解纳米颗粒穿膜在生命活动过程中的作用.     

分子间相互作用对硫醇分子膜电输运性质的影响

利用密度泛函理论和弹性散射格林函数方法,对硫醇分子膜的电学特性进行模拟.计算结果表明,由于分子间的相互作用,导致分子膜的导电能力比单分子提高2~3个数量级.分子结的导电能力随着压力增加而增加,电极距离的变化使分子与电极以及分子间的耦合增强、分子结的链内隧穿和链间隧穿几率增大,导致电流增加.     

具有电子推拉结构的多支化分子的光物理特性的研究

利用稳态光谱和飞秒时间分辨荧光亏蚀的技术,研究了不同溶剂中一系列有分子内电荷转移特性的分子的结构与光物理性质的关系,研究体系为三苯胺作为电子给体,2,1,3-苯并噻二唑作为受体的单支分子及其对应的两支和三支分子. 并结合TD-DFT计算进一步解释了实验中所观察到的现象. 三个分子相似的吸收和荧光光谱以及强的溶剂依赖光谱特性表明两支与三支分子激发态与单支分子相似,表明激发态都定域在其中一支上. 激发时多支分子内发生多维电荷转移,然后快速地定域到某一支上发射. 另一方面多支分子相对于单支分子吸收和发射光谱的红     

LB膜中聚集体的类型及其荧光特性研究

采用稳态和时间分辨芝光研究了不同类型的ＬＢ多层膜中分子聚集特性。在半花菁／花生酸交替膜中,花生酸层的隔离使得半花菁分子之间的相互作用主要发生在同一层中,形成Ｈ形成Ｈ聚集体,荧光光谱蓝移;在纯半花菁Ｙ型和Ｚ型膜中,较强的层间相互作用使分子形成Ｊ聚集体,导致荧光光谱发生显著红移。     

分子磁体与环境的纠缠和退相干

本文研究了双轴分子磁体在耗散环境中的相干量子隧穿,作为环境的声子库抑制了相干量子隧穿,从而引起分子磁体中薛定谔猫态的退相干. 而环境内部声子之间的相互作用会导致分子磁体与热库之间退耦合,于是对退相干有一定的抑制作用. 在绝热近似和非绝热近似下,借助于约化密度矩阵计算了超Ohmo耗散中分子磁体与环境之间的纠缠度,当纠缠达到最大时,相干隧穿被完全抑制.     

光谱法和分子对接法研究盐酸氨溴索与人血清白蛋白的相互作用

在模拟生理条件下,用光谱法和分子对接技术研究了盐酸氨溴索与人血清白蛋白的相互作用.不同温度下的Steen-Volmer曲线和紫外-可见吸收光谱表明:盐酸氨溴索主要以动态猝灭方式使人血清白蛋白的荧光猝灭.由热力学数据确定了两者的主要作用力类型为疏水作用力.根据F(o)rster非辐射能量转移理论,得到给体-受体间的作用距...     

Fret Studies of Conformational Changes in Heparin-Binding Peptides

FRET (Förster Resonance Energy Transfer) was applied to study structural properties of heparin-binding peptides containing the sequence XBBBXXBX where ‘X’ represents hydropathic or uncharged and ‘B’ represents basic amino acids. Internally quenched fluorogenic peptides were synthesized containing the fluorescent donor oaminobenzoic acid (o-Abz) and the acceptor dinitrophenyl ethylenediamine (Eddnp) group. Using the CONTIN computational package, distance distributions were recovered from time resolved fluorescence data, associated to end-to-end distances of the peptides. The peptides containing three or four repeat units have random structure in aqueous medium, and the interaction with low molecular weight heparin stabilized short end-to end distances. Experiments in water/trifluoroethanol (TFE) mixtures showed changes in distance distributions compatible with compact conformations stabilized above 40 % volume content of TFE in the mixture. Similar changes in distance distributions were also observed for the peptides in interaction with SDS micelles in aqueous suspensions and circular dichroism data revealed alpha-helix formation in the peptides in interaction with heparin, SDS micelles or the co-solvent TFE. The process is dependent on electrostatic and hydrogen bond interactions and the end-to-end distances obtained are smaller than expected for the peptides in linear α-helix conformation, indicating the occurrence of structural arrangements leading to additional decrease in the distances.     

The Influence of T Cell Development on Pathogen Specificity and Autoreactivity

T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein products of the major histocompatibility (MHC) gene products, which are displayed on the surface of antigen presenting cells. T?cells can also interact with peptide-MHC complexes, where the peptide is derived from host (self) proteins. A diverse repertoire of relatively self-tolerant T cell receptors is selected in the thymus. We study a model, computationally and analytically, to describe how thymic selection shapes the repertoire of T cell receptors, such that T cell receptor recognition of pathogenic peptides is both specific and degenerate. We also discuss the escape probability of autoimmune T cells from the thymus.     

Statistical interior properties of globular proteins

The character of forming long-range contacts affects the three-dimensional structure of globular proteins deeply. As the different ability to form long-range contacts between 20 types of amino acids and 4 categories of globular proteins, the statistical properties are thoroughly discussed in this paper. Two parameters N_C and N_D are defined to confine the valid residues in detail. The relationship between hydrophobicity scales and valid residue percentage of each amino acid is given in the present work and the linear functions are shown in our statistical results. It is concluded that the hydrophobicity scale defined by chemical derivatives of the amino acids and nonpolar phase of large unilamellar vesicle membranes is the most effective technique to characterise the hydrophobic behavior of amino acid residues. Meanwhile, residue percentage P_i and sequential residue length L_i of a certain protein i are calculated under different conditions. The statistical results show that the average value of P_i as well as L_i of all-α proteins has a minimum among these 4 classes of globular proteins, indicating that all-α proteins are hardly capable of forming long-range contacts one by one along their linear amino acid sequences. All-β proteins have a higher tendency to construct long-range contacts along their primary sequences related to the secondary configurations, i.e. parallel and anti-parallel configurations of β sheets. The investigation of the interior properties of globular proteins give us the connection between the three-dimensional structure and its primary sequence data or secondary configurations, and help us to understand the structure of protein and its folding process well.     

Representing environment-induced helix-coil transitions in a coarse grained peptide model

Coarse grained (CG) models are widely used in studying peptide self-assembly and nanostructure formation. One of the recurrent challenges in CG modeling is the problem of limited transferability, for example to different thermodynamic state points and system compositions. Understanding transferability is generally a prerequisite to knowing for which problems a model can be reliably used and predictive. For peptides, one crucial transferability question is whether a model reproduces the molecule's conformational response to a change in its molecular environment. This is of particular importance since CG peptide models often have to resort to auxiliary interactions that aid secondary structure formation. Such interactions take care of properties of the real system that are per se lost in the coarse graining process such as dihedral-angle correlations along the backbone or backbone hydrogen bonding. These auxiliary interactions may then easily overstabilize certain conformational propensities and therefore destroy the ability of the model to respond to stimuli and environment changes, i.e. they impede transferability. In the present paper we have investigated a short peptide with amphiphilic EALA repeats which undergoes conformational transitions between a disordered and a helical state upon a change in pH value or due to the presence of a soft apolar/polar interface. We designed a base CG peptide model that does not carry a specific (backbone) bias towards a secondary structure. This base model was combined with two typical approaches of ensuring secondary structure formation, namely a C_α-C_α-C_α-C_α pseudodihedral angle potential or a virtual site interaction that mimics hydrogen bonding. We have investigated the ability of the two resulting CG models to represent the environment-induced conformational changes in the helix-coil equilibrium of EALA. We show that with both approaches a CG peptide model can be obtained that is environment-transferable and that correctly represents the peptide's conformational response to different stimuli compared to atomistic reference simulations. The two types of auxiliary interactions lead to different kinetic behavior as well as to different structural properties for fully formed helices and folding intermediates, and we discuss the advantages and disadvantages of these approaches.     

Membranes,peptides, and disease: Unraveling the mechanisms of viral proteins with solid state nuclear magnetic resonance spectroscopy

The interplay between peptides and lipid bilayers drives crucial biological processes. For example, a critical step in the replication cycle of enveloped viruses is the fusion of the viral membrane and host cell endosomal membrane, and these fusion events are controlled by viral fusion peptides. Thus such membrane-interacting peptides are of considerable interest as potential pharmacological targets. Deeper insight is needed into the mechanisms by which fusion peptides and other viral peptides modulate their surrounding membrane environment, and also how the particular membrane environment modulates the structure and activity of these peptides. An important step toward understanding these processes is to characterize the structure of viral peptides in environments that are as biologically relevant as possible. Solid state nuclear magnetic resonance (ssNMR) is uniquely well suited to provide atomic level information on the structure and dynamics of both membrane-associated peptides as well as the lipid bilayer itself; further ssNMR can delineate the contribution of specific membrane components, such as cholesterol, or changing cellular conditions, such as a decrease in pH on membrane-associating peptides. This paper highlights recent advances in the study of three types of membrane associated viral peptides by ssNMR to illustrate the more general power of ssNMR in addressing important biological questions involving membrane proteins.     

Effective combinatorial strategy to increase affinity of carbohydrate binding by peptides

The Thomsen-Friedenreich antigen, a carcinoma-associated disaccharide involved in carcinoma cell homotypic aggregation and increased metastatic potential, has clinical value as a prognostic indicator and a marker of metastasized cells. Hence, it can reasonably be predicted that antigen-binding macromolecules are valuable clinical in vivo diagnostic/therapeutic targeting agents. Recently, we have selected first-generation antigen-binding peptides from a random peptide bacteriophage display library and have applied combinatorial affinity maturation to select functionally-maturated peptides, which target cultured carcinoma cells and inhibit carcinoma cell aggregation. In the current study we hypothesize that a targeted search of sequence space surrounding the antigen-binding consensus sequence will select unpredictable amino acid sequences in the non-consensus portions of the peptides, leading to increased affinity for the carbohydrate and greater solubility in physiological buffers. This comprehensive in vitro analysis demonstrates that preferential evolution of the amino-terminal sequence of the peptides occurred, which correlated, in structure/function studies, with the acquisition of maturated function. The maturated peptides are more soluble than the earlier peptides. Studies of peptide binding to the disaccharide indicate that two maturated peptides (P-30-1, F03) have higher affinity for the antigen and bind with higher intensity to the surface of cultured human carcinoma cells than the first-generation peptides. The results support our hypothesis that affinity maturation can improve carbohydrate binding by peptides and have theoretical importance as the first report of maturation of carbohydrate-binding affinity in a small, soluble peptide.     

Directing the phase behavior of polyelectrolyte complexes using chiral patterned peptides

Polyelectrolyte complexes (PECs) have a broad range of promising applications as soft materials due to their self-assembly and diversity of structure and chemical composition. Peptide polymer PECs are highly biocompatible and biodegradable, making them particularly useful for encapsulation of food additives and flavors, micellar drug delivery, medical and underwater adhesives, fetal membrane patches, and scaffolds for cell growth in tissue engineering. While parameters affecting PEC formation and stability in regards to charge effects are well researched, little is known about the effects of van der Waals interactions, hydrogen bonding, and secondary structure in these materials. Peptide chirality provides a unique opportunity to manipulate PEC phase to modulate the amount of solid-like (precipitate) or liquid-like (coacervate) character by influencing hydrogen bonding interactions among peptide chains. In previous work, we showed that chiral peptides form solid complexes, while complexes with even one racemic peptide were fluid. This raised the interesting question of how long a homochiral sequence must be to result in solid phase formation. In this work, we designed chiral patterned peptides of polyglutamic acid and polylysine ranging from 50 to 90% L-chiral residues with increasing numbers of sequential L-chiral residues before a chirality change. These polymers were mixed together to form PECs. We observed that 8 or more sequential L-chiral residues are necessary to achieve both the appearance of a precipitate phase and sustained β-sheets in the complex, as determined by optical imaging and FTIR Spectroscopy. Less homochiral content results in formation of a coacervate phase. Thus, we show that chiral sequence can be used to control the phase transition of PECs. Understanding how to manipulate PEC phase using chiral sequence as presented here may enable tuning of the material properties to achieve the desired mechanical strength for coatings and polymer brushes, or the most effective molecular release kinetics for drug delivery applications, for example.     

Nonlinear signal transduction network with multistate

Signal transduction is an important and basic mechanism to cell life activities. The stochastic state transition of receptor induces the release of signaling molecular, which triggers the state transition of other receptors. It constructs a nonlinear sigaling network, and leads to robust switchlike properties which are critical to biological function. Network architectures and state transitions of receptor affect the performance of this biological network. In this work, we perform a study of nonlinear signaling on biological polymorphic network by analyzing network dynamics of the Ca²⁺-induced Ca²⁺ release (CICR) mechanism, where fast and slow processes are involved and the receptor has four conformational states. Three types of networks, Erdös-Rényi (ER) network, Watts-Strogatz (WS) network, and BaraBási-Albert (BA) network, are considered with different parameters. The dynamics of the biological networks exhibit different patterns at different time scales. At short time scale, the second open state is essential to reproduce the quasi-bistable regime, which emerges at a critical strength of connection for all three states involved in the fast processes and disappears at another critical point. The pattern at short time scale is not sensitive to the network architecture. At long time scale, only monostable regime is observed, and difference of network architectures affects the results more seriously. Our finding identifies features of nonlinear signaling networks with multistate that may underlie their biological function.