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多肽及蛋白质的插膜机制是目前分子生物学、细胞生物学研究中十分活跃的领域之一。本文通过荧光、圆二色等波谱学技术,深入地探讨了处于不同构象状态的毒素蛋白分子与磷脂膜作用后的构象变化。结果表明：带负电荷的磷脂膜对处于不同构象状态的ＣｏｌｉｃｉｎＥ１分子的二级结构有较强的诱导作用;这种作用是电荷依赖性的。处于不同构象状态的毒素蛋白分子在磷脂膜的诱导下均可不同程度恢复其天然状态下插膜时的构象。不同磷脂对ＣｏｌｉｃｉｎＥ１分子诱导的强弱依次为ＤＭＰＧ＞ＤＭＰＥ＞ＤＭＰＣ。ＣｏｌｉｃｉｎＥ１分子与磷脂膜的结合是紧密的,结合后的蛋白质有较强的抗变性能力。 相似文献
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大肠杆菌的维生素B12转运蛋白（BtuCD）属于ATP结合盒转运蛋白,目前对BtuCD转运底物进入胞质内的确切机制仍不清楚．本研究将BtuCD的跨膜结构域BtuC插入棕榈酰油酸磷脂酰胆碱（POPC）双层膜中,通过MD模拟来研究BtuC的功能性运动．通过超过57ns的MD模拟得到了稳定的蛋白质-脂双层膜体系．模拟结果发现,POPC双层膜能够调整其厚度以适应其中的BtuC．反映脂双层膜性质的两个参数,即每个脂分子的面积和脂双层膜厚度,均与实验测得数据吻合．通过对从MD模拟提取的轨迹进行主成分分析（PCA）,使得能从原子水平上了解BtuC的几种主要运动模式．结果表明,尽管BtuC的几种主要运动模式各不相同,却都实现了跨膜通道维度的改变,控制通道开121的打开和闭合．这些BtuC运动模式和与其相互作用的BtuF和BtuD的功能性运动很好的偶合．BtuC的运动主要体现在周质一侧的区域,控制跨膜通道在该侧开口的大小．MD模拟过程中,这一侧开口可以比晶体结构反映的“开放”状态更开放．在胞质一侧,并未观察到通道开口的明显变化．意外的是,尽管BtuC两个结构域具有相同的序列和类似的高级结构,但它们在运动上却有明显差异．这些结果有助于在原子水平上理解底物的转运机制． 相似文献
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目的 壳聚糖（chitosan,CS）是一种天然的广谱抗菌活性物质。现有研究表明,壳聚糖与细菌细胞膜的相互作用是其发挥抗菌功能的关键。受限于传统实验技术的表征能力,壳聚糖与细菌细胞膜相互作用的具体机制仍有待研究。本文旨在研究壳聚糖与细菌细胞膜相互作用的分子机制。方法 本研究利用全原子分子动力学模拟技术主要探究了完全脱乙酰化的不同聚合度壳聚糖（八聚糖、十二聚糖和十六聚糖）与革兰氏阴性菌外膜（outer membrane,OM）和革兰氏阳性菌质膜（cytoplasmic membrane,CM）相互作用的动态过程。结果 壳聚糖主要依靠其氨基、碳6位羟基和碳3位羟基与OM和CM的头部极性区发生快速结合。随后壳聚糖末端糖基单元倾向于插入OM内部,深度约1 nm,并与脂质分子脂肪酸链上的羰基形成稳定的氢键相互作用。与之相比,壳聚糖分子难以稳定地插入CM内部。壳聚糖结合对膜结构性质产生影响,主要表现在降低OM和CM的单分子脂质面积,显著减少OM和CM极性区的Ca2+和Na+数目,破坏阳离子介导的脂质间相互作用。结论 本研究证明,壳聚糖带正电的氨基基团是介导其与膜相互作用的关键,并破环脂质间的相互作... 相似文献
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目的:对人乳头瘤病毒HPV16,18中E6蛋白结构进行分子模拟和分析,寻找可以作为蛋白-配体相互作用的关键结构区域。方法:以HPV16 E6蛋白为模板,对HPV18 E6蛋白进行同源建模,对构建的HPV18 E6模型以及晶体结构模型HPV16 E6进行分子动力学模拟,通过微观上的loop环分析和宏观上的整体运动分析研究了HPV18 E6与HPV16 E6在溶剂环境下结构变化的异同。结果:发现靠近N端loop环在蛋白-配体结合过程中能介导控制配体、水、离子进出的\"门控\"的作用,解释了两个蛋白在水溶剂中的运动构象的变化。结论:本研究解释了HPV16 E6与HPV18 E6两个蛋白在溶剂中的运动机制,并发现了loop环在其中扮演\"门控\"的作用,解释了两个蛋白在水溶剂中的运动构象的变化,该发现能够为基于两个蛋白为靶点的药物设计提供理论依据。 相似文献
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采用GROMOS43A1力场,用温度副本交换分子动力学模拟方法研究水溶液中H1小肽在4个不同温度下的结构特征.选择H1小肽的初始构象分别为α螺旋和β折叠片,完成了两组独立的36个温度副本交换的分子动力学模拟,一组从α螺旋出发的模拟用来对该小肽的结构特征进行研究,另一组从β折叠片出发的模拟用于验证构象采样的收敛性,每个副本的模拟时间为300ns,共计模拟时间长达21.6μs.在此基础上,研究了H1小肽在温度300K、330K、350K和370K下的结构特征,分析了其主链二面角分布、天然氢键数、β转角的形成概率以及不同温度下偏好采样构象的变化特征等.模拟结果表明,在4个不同温度下,均能够采样到同β折叠片结构的Cα原子均方根偏差最小为0.05nm的构象类,该构象类在4个不同温度300K、330K、350K和370K下分别包含了全部构象的39%、23%、13%和11%.GROMOS43A1力场在刻画小肽的结构方面具有一定的精度,但是在描述氢键方面仍需要加强,H1小肽在不同温度下结构特征的比较能够为分子力场的优化提供重要的帮助. 相似文献
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病毒通过自身蛋白与宿主蛋白间的相互作用,营造一种适合于其转化、增殖的体内环境,从而引起一系列疾病的过程。人乳头瘤病毒(HPV)与某些肿瘤发病关系密切,分子机制研究表明,其表达的早期蛋白E6是HPV参与细胞恶性转化的主要蛋白。含有PDZ结构域的蛋白质是细胞内广泛存在的一类蛋白质。本文综述了人乳头瘤病毒的E6蛋白和宿主细胞的PDZ蛋白间的相互作用,讨论了这种作用引发的细胞内生化生理改变及其应用前景。 相似文献
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分子伴侣蛋白Hsp70氮端核苷酸结合域（NBD, nucleotide-binding domain）的ATP酶活性变化对其行使分子伴侣功能具有重要作用。本文采用分子动力学模拟方法研究酵母分子伴侣Hsp70氮端NBD内残基A17,R23,G32和R167点突变对其ATP酶活性区域构象影响及功能关系。结果表明,突变体A17V,T23H,G32S的ATP结合口袋袋口的loopl（第一个转角,连接p1与p2）结构柔性增强,活性残基T11侧链明显向内移动,从而更加接近ATP的γ-磷酸基团,更容易使ATP水解。这可能蕞终导致ATP酶活性增强,从而引起分子伴侣功能的变化。 相似文献
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大肠杆菌分子伴侣蛋白Dna K氮端核苷酸结合域(NBD,nucleotide-binding domain)的II-A和II-B子域之间的一些高度保守的扭链残基突变后(I202A,S203A,G223A,L227A,G228A),其ATPase活性也发生变化原因不清楚。我们通过同源建模的方法构建NBD与小分子ATP相互作用的各蛋白模型,使用分子动力学模拟方法研各模型的结构变化并尝试找出其与ATPase活性变化的关系。结果表明,除L227A外,所有突变模型T11烃基与ATP-γ磷酸基团间的距离与活性变化间具有明显规律;但是所有模型中,能影响与Dna J结合,从而影响ATPase活性的β220(214-221)部分的紧致性变化符合规律,进一步的蛋白对接实验证实了这一点,所以这些扭链残基突变体可能主要是通过这两个部分的变化,引起ATPase活性的改变。 相似文献
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Arezoo Rahmanpour Mohammad Mehdi Ghahremanpour Majid Erfani Moghaddam 《Journal of biomolecular structure & dynamics》2013,31(12):1393-1403
Plasma membrane of each micro-organism has a unique set of lipid composition as a consequence of the environmental adaptation or a response to exposure to antimicrobial peptides (AMPs) as antibiotic agents. Understanding the relationship between lipid composition and action of antimicrobial peptides or considering how different lipid bilayers respond to AMPs may help us design more effective peptide drugs in the future. In this contribution, we intend to elucidate how two currently used membrane models, namely palmitoyl-oleoyl-phosphtidylglycerol (POPG) and 1-palmitoyl-oleoyl-glycero-phosphocholine (POPC), respond to antimicrobial peptide Piscidin-1 (Pis-1).The computed density profile of the peptide as it moves from the bulk solvent toward the membrane core suggests that Pis-1 penetrates into the POPG bilayer less than the POPC membrane. Furthermore, we showed that the two model membranes used in this study have different behavior in the presence of Pis-1. Hence, we suggest that membrane composition could be an important factor in determining lytic ability of peptide drugs to kill a unique bacterial species.An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:37 相似文献
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A 13-residue alpha-helical peptide (K6L5WP), designed from Leu6-->Pro substitution of a hemolytic alpha-helical peptide (K6L6W), exhibited strong antibacterial activity (MIC: 2 to approximately 4 microM against three gram-positives and three gram-negatives) comparable to that of melittin but had no hemolytic activity. Tryptophan fluorescence studies indicated bacterial selectivity of K6L5WP is closely related to the selective interaction with negatively charged phospholipids on the surface of bacterial cells. These results suggested that the central Pro6 in K6L5WP plays an important role in its bacterial cell selectivity. In conclusion, K6L5WP with antibacterial selectivity may serve as an attractive candidate for the development of antimicrobial agents. 相似文献
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Buforin II is a 21-amino acid polycationic antimicrobial peptide derived from a peptide originally isolated from the stomach tissue of the Asian toad Bufo bufo gargarizans. It is hypothesized to target a wide range of bacteria by translocating into cells without membrane permeabilization and binding to nucleic acids. Previous research found that the structure and membrane interactions of buforin II are related to lipid composition. In this study, we used molecular dynamics (MD) simulations along with lipid vesicle experiments to gain insight into how buforin II interacts differently with phosphatidylcholine (PC), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) lipids. Fluorescent spectroscopic measurements agreed with the previous assertion that buforin II does not interact with pure PC vesicles. Nonetheless, the reduced entry of the peptide into anionic PG membranes versus neutral PC membranes during simulations correlates with the experimentally observed reduction in BF2 translocation through pure PG membranes. Simulations showing membrane entry into PC also provide insight into how buforin II may initially penetrate cell membranes. Our MD simulations also allowed us to consider how neutral PE lipids affect the peptide differently than PC. In particular, the peptide had a more helical secondary structure in simulations with PE lipids. A change in structure was also apparent in circular dichroism measurements. PE also reduced membrane entry in simulations, which correlates with decreased translocation in the presence of PE observed in previous studies. Together, these results provide molecular-level insight into how lipid composition can affect buforin II structure and function and will be useful in efforts to design peptides with desired antimicrobial and cell-penetrating properties. 相似文献
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The membrane interaction of two beta peptides was studied using a surface plasmon resonance biosensor. The two peptides are β‐17, a novel β‐amino acid based antimicrobial peptide and the corresponding scrambled‐β17—a non‐antimicrobial β‐peptide analogue. Membrane interaction studies were performed with a series of phospholipid mixtures which mimic either mammalian cells (high in phosphatidylcholine and cholesterol) or microbial cells (high in phosphatidylethanolamine and phosphatidylglycerol). The results were compared with the membrane binding of the well‐characterized antimicrobial peptide magainin 2. The secondary structure of these peptides were also determined in each lipid mixture by circular dichroism and correlated with the membrane‐binding properties. Both β‐17 and the scrambled peptide have the same peptide length, charge and showed a similar secondary structure in both aqueous buffer and in the presence of liposomes. Both peptides also bound to a similar level on each membrane mixture, showing that the dramatic difference in biological activity is not based on the amount of peptide bound but rather differences in the degree of insertion and rate of membrane dissociation. Although β‐17 and the scrambled β‐17 peptide exhibited similar binding properties on all membrane mimics, both β‐peptides bound more to all membranes compared with magainin 2. Overall, the results further reveal the significant interplay between peptide amphipathicity and secondary structure induction on membrane binding. © 2009 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 92: 554–564, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com 相似文献
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Marcia Perez Dos Santos Cabrera Manoel Arcisio‐Miranda Sabrina Thais Broggio Costa Katsuhiro Konno José Roberto Ruggiero Joaquim Procopio João Ruggiero Neto 《Journal of peptide science》2008,14(6):661-669
Anoplin, an antimicrobial, helical decapeptide from wasp venom, looses its biological activities by mere deamidation of its C-terminus. Secondary structure determination, by circular dichroism spectroscopy in amphipathic environments, and lytic activity in zwitterionic and anionic vesicles showed quite similar results for the amidated and the carboxylated forms of the peptide. The deamidation of the C-terminus introduced a negative charge at an all-positive charged peptide, causing a loss of amphipathicity, as indicated by molecular dynamics simulations in TFE/water mixtures and this subtle modification in a peptide's primary structure disturbed the interaction with bilayers and biological membranes. Although being poorly lytic, the amidated form, but not the carboxylated, presented ion channel-like activity on anionic bilayers with a well-defined conductance step; at approximately the same concentration it showed antimicrobial activity. The pores remain open at trans-negative potentials, preferentially conducting cations, and this situation is equivalent to the interaction of the peptide with bacterial membranes that also maintain a high negative potential inside. 相似文献
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To examine the conformational properties in aqueous solution of a 15-residue peptide that is a potential pharmacophore for AIDS vaccine development, molecular dynamics simulations were performed in water starting from structures determined experimentally in three different organic solvents. Convergence characteristics of the simulation are examined in Cartesian and conformational spaces. In addition, novel analysis tools are employed including a multidimensional scaling method to represent the distance between trajectory frames. As these methods are based on a variety of physical parameters, they provide a useful cross-check on the structural convergence. Theoretical two-dimensional (2D) 1H-NMR spectra are also generated. These are superficially quite different in appearance, demonstrating that backbone similarities difficult to identify by visual inspection of 2D NMR data can be revealed using the methods described here. 相似文献
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José-Luis Velasco-Bolom Gerardo Corzo 《Journal of biomolecular structure & dynamics》2020,38(10):2928-2938
AbstractMost helical antimicrobial peptides (AMPs) are usually unfolded in aqueous solution; however they acquire their secondary structure in the presence of a hydrophobic environment such as lipid membranes. Being the biological membranes the main target of many AMPs it is necessary to understand their way of action. Pandinin 2 (Pin2) is an alpha-helical AMP isolated from the venom of the African scorpion Pandinus imperator which shows high antimicrobial activity against Gram-positive bacteria and it is less active against Gram-negative bacteria, nevertheless, it has strong hemolytic activity. Its chemically synthesized Pin2GVG analog has low hemolytic activity while keeping its antimicrobial activity. With the aim of exploring the partition and subsequent folding of these peptides, in this work we report the results of extensive molecular dynamics simulations of Pin2 and Pin2GVG peptides in the presence of 2 hydrophobic environments such as dodecyl-phosphocholine (DPC) micelle and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocoline (POPC) membrane. Our results indicate that Pin2 folds in DPC with a 79% of alpha-helical content, which is in agreement with the experimental results, while in POPC it has 62.5% of alpha-helical content. On the other hand, Pin2GVG presents a higher percentage of alpha-helical structure in POPC and a smaller content in DPC when compared with Pin2. These results can help to better choose the starting structures in future molecular dynamics simulations of AMPs, because these peptides can adopt slightly different conformations depending on the hydrophobic environment.Communicated by Ramaswamy H. Sarma 相似文献
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Antimicrobial peptides are promising alternative to traditional antibiotics and antitumor drugs for the battle against new antibiotic resistant bacteria strains and cancer maladies. The study of their structural and dynamics properties at physiological conditions can help to understand their stability, delivery mechanisms, and activity in the human body. In this article, we have used molecular dynamics simulations to study the effects of solvent environment, temperature, ions concentration, and peptide concentration on the structural properties of the antimicrobial hybrid peptide Cecropin A–Magainin 2. In TFE/water mixtures, the structure of the peptide retained α‐helix contents and an average hinge angle in close agreement with the experimental NMR and CD measurements reported in literature. Compared to the TFE/water mixture, the peptide simulated at the same ionic concentration lost most of its α‐helix structure. The increase of peptide concentration at both 300 and 310 K resulted in the peptide aggregation. The peptides in the complex retained the initial N‐ter α‐helix segment during all the simulation. The α‐helix stabilization is further enhanced in the high salt concentration simulations. The peptide aggregation was not observed in TFE/water mixture simulations and, the peptide aggregate, obtained from the water simulation, simulated in the same conditions did dissolve within few tens of nanoseconds. The results of this study provide insights at molecular level on the structural and dynamics properties of the CA‐MA peptide at physiological and membrane mimic conditions that can help to better understand its delivery and interaction with biological interfaces. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 1–14, 2015. 相似文献
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In this paper, the N-terminus of glycoprotein-41, the HIV-1 fusion peptide, was studied by molecular dynamics simulations in an explicit sodium dodecyl sulfate micelle. The simulation provides a detailed picture of the equilibrium structure and peptide stability as it interacts with the micelle. The equilibrium location of the peptide shows the peptide at the surface of the micelle with hydrophobic residues interacting with the micelle's core. At equilibrium, the peptide adopts an alpha-helical structure from residues 5-16 and a type-1 beta-turn from 17-20 with the other residues exhibiting more flexible conformations. The primary hydrophobic interactions with the micelle are from the leucine and phenylalanine residues (Leu-7, Phe-8, Leu-9, Phe-11, Leu-12) while the alanine and glycine residues (Ala-1, Gly-3, Gly-5, Ala-6, Gly-10, Gly-13, Ala-14, Ala-15, Gly-16, Gly-10, Ala-21) interact favorably with water molecules. The results suggest that Phe-8, part of the highly conserved FLG motif of the fusion peptide, plays a key role in the interaction of the peptide with membranes. Our simulations corroborate experimental investigations of the fusion peptide in SDS micelles, providing a high-resolution picture that explains the experimental findings. 相似文献
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Yu‐ming M. Huang Yinglong Miao Jason Munguia Leo Lin Victor Nizet J. Andrew McCammon 《Protein science : a publication of the Protein Society》2016,25(8):1430-1437
The composition of the outer membrane in Gram‐negative bacteria is asymmetric, with the lipopolysaccharides found in the outer leaflet and phospholipids in the inner leaflet. The MlaC protein transfers phospholipids from the outer to inner membrane to maintain such lipid asymmetry in the Mla pathway. In this work, we have performed molecular dynamics simulations on apo and phospholipid‐bound systems to study the dynamical properties of MlaC. Our simulations show that the phospholipid forms hydrophobic interactions with the protein. Residues surrounding the entrance of the binding site exhibit correlated motions to control the site opening and closing. Lipid binding leads to increase of the binding pocket volume and precludes entry of the water molecules. However, in the absence of the phospholipid, water molecules can freely move in and out of the binding site when the pocket is open. Dehydration occurs when the pocket closes. This study provides dynamic information of the MlaC protein and may facilitate the design of antibiotics against the Mla pathway of Gram‐negative bacteria. 相似文献