Prediction of protein conformational freedom from distance constraints

A method is presented that generates random protein structures that fulfil a set of upper and lower interatomic distance limits. These limits depend on distances measured in experimental structures and the strength of the interatomic interaction. Structural differences between generated structures are similar to those obtained from experiment and from MD simulation. Although detailed aspects of dynamical mechanisms are not covered and the extent of variations are only estimated in a relative sense, applications to an IgG-binding domain, an SH3 binding domain, HPr, calmodulin, and lysozyme are presented which illustrate the use of the method as a fast and simple way to predict structural variability in proteins. The method may be used to support the design of mutants, when structural fluctuations for a large number of mutants are to be screened. The results suggest that motional freedom in proteins is ruled largely by a set of simple geometric constraints. Proteins 29:240–251, 1997. © 1997 Wiley-Liss, Inc.     

Role of methyl groups in dynamics and evolution of biomolecules

Recent studies have discovered strong differences between the dynamics of nucleic acids (RNA and DNA) and proteins, especially at low hydration and low temperatures. This difference is caused primarily by dynamics of methyl groups that are abundant in proteins, but are absent or very rare in RNA and DNA. In this paper, we present a hypothesis regarding the role of methyl groups as intrinsic plasticizers in proteins and their evolutionary selection to facilitate protein dynamics and activity. We demonstrate the profound effect methyl groups have on protein dynamics relative to nucleic acid dynamics, and note the apparent correlation of methyl group content in protein classes and their need for molecular flexibility. Moreover, we note the fastest methyl groups of some enzymes appear around dynamical centers such as hinges or active sites. Methyl groups are also of tremendous importance from a hydrophobicity/folding/entropy perspective. These significant roles, however, complement our hypothesis rather than preclude the recognition of methyl groups in the dynamics and evolution of biomolecules.     

海三棱蔗草种群的密度与生物量动态

本文研究了上海市南汇县东海农场海堤外侧滩涂上海三棱藨草种群的密度动态,高度生长动态、生物量动态以及它们之间及其与环境之间的相互关系。研究结果表明：在环境条件相对稳定的地带A和B内,海三棱藨草种群的高度、高度生长和生物量在生长期内符合Logisfic增长。种群生物量动态与密度动态可分为3个阶段,其中阶段Ⅱ符合Yoda等提出的-3/2自疏定律。地带B为海三棱藨草种群生长的最适地带。地带C内生境条件极不稳定,种群的数量动态变化亦相当剧烈。在不同环境条件下,密度制约因素和非密度制约因素对种群数量动态的相对作用是不同的。在环境条件较稳定的生境中(地带A和B),密度制约因素是决定种群数量动态的主要因素;在环境条件变化剧烈的生境中(地带C),非密度制约因素是决定种群数量动态的主要因素。     

Spatial and temporal dynamics of the cardiac mitochondrial proteome

Mitochondrial proteins alter in their composition and quantity drastically through time and space in correspondence to changing energy demands and cellular signaling events. The integrity and permutations of this dynamism are increasingly recognized to impact the functions of the cardiac proteome in health and disease. This article provides an overview on recent advances in defining the spatial and temporal dynamics of mitochondrial proteins in the heart. Proteomics techniques to characterize dynamics on a proteome scale are reviewed and the physiological consequences of altered mitochondrial protein dynamics are discussed. Lastly, we offer our perspectives on the unmet challenges in translating mitochondrial dynamics markers into the clinic.     

Cooperative Thermal Denaturation of the Assembly Origin Region of TMV RNA

Abstract

The assembly origin (AO) region of the tobacco mosaic virus RNA melts in an unusually narrow(2.5°C) temperature range. In an 0.01 M phosphate buffer the melting temperature of AO was found to be 41.5°C. This value corresponds to the regions with the most stable secondary/tertiary structure of the whole TMV RNA molecule. It is assumed that the AO region has a specific tertiary structure, which is maintained by the long-range interactions as well as by interactions of the pseudoknot type.     

Nudged elastic band calculation of minimal energy paths for the conformational change of a GG non-canonical pair

The nudged elastic band (NEB) technique has been implemented in AMBER to calculate low-energy paths for conformational changes. A novel simulated annealing protocol that does not require an initial hypothesis for the path is used to sample low-energy paths. This was used to study the conformational change of an RNA cis Watson-Crick/Hoogsteen GG non-canonical pair, with one G syn around the glycosidic bond and the other anti. A previous solution structure, determined by NMR-constrained modeling, demonstrated that the GG pairs change from (syn)G-(anti)G to (anti)G-(syn)G in the context of duplex r(GCAGGCGUGC) on the millisecond timescale. The set of low-energy paths found by NEB show that each G flips independently around the glycosidic bond, with the anti G flipping to syn first. Guanine bases flip without opening adjacent base-pairs by protruding into the major groove, accommodated by a transient change by the ribose to C2'-exo sugar pucker. Hydrogen bonds between bases and the backbone, which lower the energetic barrier to flipping, are observed along the path. The results show the plasticity of RNA base-pairs in helices, which is important for biological processes, including mismatch repair, protein recognition, and translation. The modeling of the GG conformational change also demonstrates that NEB can be used to discover non-trivial paths for macromolecules and therefore NEB can be used as an exploratory method for predicting putative conformational change paths.     

Molecular dynamics studies of alanine racemase: a structural model for drug design

Alanine racemase (AlaR) is a bacterial enzyme that catalyzes the interconversion of L- and D-alanine, which is an essential constituent of the peptidoglycan layer of the bacterial cell wall and requires pyridoxal 5'-phosphate (PLP) as a cofactor. The enzyme is universal to bacteria, including mycobacteria, making it an attractive target for drug design. To investigate the effects of flexibility on the binding modes of the substrate and an inhibitor and to analyze how the active site is affected by the presence of the substrate versus inhibitor, a molecular dynamics simulation on the full AlaR dimer from Bacillus stearothermophilus (pdb code: 1SFT) with a D-alanine molecule in one active site and the noncovalent inhibitor, propionate, in the second site has been carried out. Within the time scale of the simulation, we show that the active site becomes more stabilized in the presence of substrate versus inhibitor. The results of this simulation are in agreement with the proposed mechanism of alanine racemase reaction in which the substrate carboxyl group directly participates in the catalysis by acting cooperatively with Tyr 265' and Lys 39. A structural water molecule in contact with both substrate and inhibitor (i.e., in both active sites) and bridging residues in both active sites was identified. It shows a remarkably low mobility and does not exchange with bulk water. This water molecule can be taken into account for the design of specific AlaR inhibitors by either utilizing it as a bridging group or displacing it with an inhibitor atom. The results presented here provide insights into the dynamics of the alanine racemase in the presence of substrate/inhibitor, which will be used for the rational design of novel inhibitors.     

Breaths,Twists, and Turns of Atomistic Nucleosomes

Gene regulation programs establish cellular identity and rely on dynamic changes in the structural packaging of genomic DNA. The DNA is packaged in chromatin, which is formed from arrays of nucleosomes displaying different degree of compaction and different lengths of inter-nucleosomal linker DNA. The nucleosome represents the repetitive unit of chromatin and is formed by wrapping 145–147 basepairs of DNA around an octamer of histone proteins. Each of the four histones is present twice and has a structured core and intrinsically disordered terminal tails. Chromatin dynamics are triggered by inter- and intra-nucleosome motions that are controlled by the DNA sequence, the interactions between the histone core and the DNA, and the conformations, positions, and DNA interactions of the histone tails. Understanding chromatin dynamics requires studying all these features at the highest possible resolution. For this, molecular dynamics simulations can be used as a powerful complement or alternative to experimental approaches, from which it is often very challenging to characterize the structural features and atomic interactions controlling nucleosome motions. Molecular dynamics simulations can be performed at different resolutions, by coarse graining the molecular system with varying levels of details. Here we review the successes and the remaining challenges of the application of atomic resolution simulations to study the structure and dynamics of nucleosomes and their complexes with interacting partners.     

The role of disulfide bonds and N‐terminus in the structural properties of hepcidins: Insights from molecular dynamics simulations

The main purpose of this work is to analyse, by means of molecular dynamics (MD) simulations both structural and mechanical‐dynamical differences between Hepcidin‐20 and Hepcidin‐25 in both oxidized and reduced states in aqueous solution. Results indicate that the presence of disulfide bonds is essential, in both peptides, for maintaining their β‐hairpin motif. As a matter of fact, the lack of this intra‐peptide covalent interactions produces an almost immediate deviation from the oxidized, plausibly active, structure in both the systems. Interestingly, reduced Hepcidin‐25 turns out to be characterized by a highly fluctuating structure which is found to rapidly span a large number of configurations at equilibrium. On the other hand, loss of disulfide bonds in the shorter peptide, results in a more compact and relatively rigid double‐turn structure. Comparison of mechanical–dynamical properties and sidechains–sidechains interactions in oxidized Hepcidin‐20 and Hepcidin‐25 strongly suggest also the key role of N‐terminus in the aggregation tendency of Hepcidin‐25. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 917–926, 2010.     

Emerging computational approaches for the study of protein allostery

Allosteric regulation of protein function is key in controlling cellular processes so its underlying mechanisms are of primary concern to research in areas spanning protein engineering and drug design. However, due to the complex nature of allosteric mechanisms, a clear and predictive understanding of the relationship between protein structure and allosteric function remains elusive. Well established experimental approaches are available to offer a limited degree of characterization of mechanical properties within proteins, but the analytical capabilities of computational methods are evolving rapidly in their ability to accurately define the subtle and concerted structural dynamics that comprise allostery. This review includes a brief overview of allostery in proteins and an exploration of relevant experimental methods. An explanation of the transition from experimental toward computational methods for allostery is discussed, followed by a review of existing and emerging methods.     

海三棱藨草种群的密度与生物量动态

本文研究了上海市南汇县东海农场海堤外侧滩涂上海三棱藨草种群的密度动态、高度生长动态、生物量动态以及它们之间及其与环境之间的相互关系。研究结果表明:在环境条件相对稳定的地带A和B内,海三棱藨草种群的高度、高度生长和生物量在生长期内符合Logisfis增长。种群生物量动态与密度动态可分为3个阶段,其中阶段Ⅱ符合Yoda等提出的-3/2自疏定律。地带B为海三棱藨草种群生长的最适地带。地带C内生境条件极不稳定,种群的数量动态变化亦相当剧烈。在不同环境条件下,密度制约因素和非密度制约因素对种群数量动态的相对作用是不同的。在环境条件较稳定的生境中(地带A和B),密度制约因素是决定种群数量动态的主要因素;在环境条件变化剧烈的生境中(地带C),非密度制约因素是决定种群数量动态的主要因素。     

A diverse view of protein dynamics from NMR studies of HIV-1 protease flaps

Internal motion in proteins fulfills a multitude of roles in biological processes. NMR spectroscopy has been applied to elucidate protein dynamics at the atomic level, albeit at a low resolution, and is often complemented by molecular dynamics simulation. However, it is critical to justify the consistency between simulation results and conclusions often drawn from multiple experiments in which uncertainties arising from assumed motional models may not be explicitly evaluated. To understand the role of the flaps of HIV-1 protease dimer in substrate recognition and protease function, many molecular dynamics simulations have been performed. The simulations have resulted in various proposed models of the flap dynamics, some of which are more consistent than others with our working model previously derived from experiments. However, using the working model to discriminate among the simulation results is not straightforward because the working model was derived from a combination of NMR experiments and crystal structure data. In this study, we use the NMR chemical shifts and relaxation data of the protease "monomer" rather than structural data to narrow down the possible conformations of the flaps of the "dimer". For the first time, we show that the tips of the flaps in the unliganded protease dimer interact with each other in solution. Accordingly, we discuss the consistency of the simulations with the model derived from all experimental data.     

Essential dynamics of proteins

Analysis of extended molecular dynamics (MD) simulations of lysozyme in vacuo and in aqueous solution reveals that it is possible to separate the configurational space into two subspaces: (1) an “essential” subspace containing only a few degrees of freedom in which anharmonic motion occurs that comprises most of the positional fluctuations; and (2) the remaining space in which the motion has a narrow Gaussian distribution and which can be considered as “physically constrained.” If overall translation and rotation are eliminated, the two spaces can be constructed by a simple linear transformation in Cartesian coordinate space, which remains valid over several hundred picoseconds. The transformation follows from the covariance matrix of the positional deviations. The essential degrees of freedom seem to describe motions which are relevant for the function of the protein, while the physically constrained subspace merely describes irrelevant local fluctuations. The near-constraint behavior of the latter subspace allows the separation of equations of motion and promises the possibility of investigating independently the essential space and performing dynamic simulations only in this reduced space. © 1993 Wiley-Liss, Inc.     

Brownian Dynamics Simulation of DNA Gel Electrophoresis

Abstract

Brownian dynamics computer simulation technique was applied to investigate DNA dynamics in gel electrophoresis. Under a constant electric field of moderate strength, large DNA chains take stretched and contracted conformations alternatively during the migration. The conformation change is quasi-periodic under certain conditions, and its frequency is closely related to the experimentally-found suitable frequency of pulse field gel electrophoresis.     

自然种群中混沌的检测及其在种群动态研究中的意义

混沌现象广泛地存在于自然界,20世纪70年代以来,通过大量的生物模型模拟说明混沌也存在于生物系统中。几十年来生态学家一直在努力寻找混沌在自然生态系统存在的证据,但所获不多,这是源于自然的现实还是由于检测方法的不当和数据的局限?一直困扰着生态学家,自然界中对混沌的检测成为一个要点,也是一个难点。在概述混沌概念和性质的基础上,着重介绍目前在自然生态系统检测混沌的方法,对各种方法的应用条件和范围进行了概述。这些方法包括功率谱法、时间序列的自相关函数分析、模型参数估计、庞加莱截面法、全局和局域李雅普若夫特征指数的估计、吸引子关联维的确定、非线性预测。大量研究结果显示,虽然在自然界检测到的混沌的例子还不多,但其存在却是不容怀疑的。问题是什么样的系统在什么样的条件下会出现混沌?研究表明食物链的结构、种群的迁入和迁出、环境噪音都会对种群的复杂性动态特征产生影响。混沌动态可能对产生系统的多样性和适应性有利,它比随机系统对外界干扰的抵抗能力更强。自然界的变化和系统的维持是持续性和混沌相互矛盾统一的结果。害虫种群复杂性动态的研究为害虫的管理提供了更多的理论依据。混沌控制的理论和方法有可能为害虫管理提供新的思路和途径。在孤立的种群中,混沌会增加种群的灭绝概率,而在集合种群中,混沌动态降低了各局域种群的同步性和同时灭绝的倾向,所以混沌虽然能增加局域种群灭绝的概率,但却能减少整个集合种群灭绝的概率。系统结构及其时空动态与混沌及种群灭绝之间的关系,是保护生物学及生物多样性保护研究的一个重要方面。今后的研究应更多地从种群、群落、生态系统及景观不同层次上的时空动态入手,利用3S等信息技术和空间动态分析方法,研究复杂性动态产生的条件及其在系统调控中的作用机制。     

Resident-invader dynamics and the coexistence of similar strategies

We study the resident-invader dynamics for a given class of models of unstructured populations of finite-dimensional strategies. We prove various results on the existence and uniqueness of -limit sets in the interior of the resident-invader population state space, and we classify the generically possible types of dynamics in terms of the invasion conditions when the resident and invader strategies are similar to one another.This work was supported by the Academy of Finland     

Co‐occurrence and seasonal and environmental distributions of the sandflies Lutzomyia longipalpis and Nyssomyia whitmani in the city of Puerto Iguazú, northeastern Argentina

The aim of this work was to study the distribution of Phlebotominae (Diptera: Psycodidade) abundance in time and space in an area in northeastern Argentina with vector transmission of visceral and tegumentary leishmaniasis. For this, 51 households were selected using a ‘worst scenario’ criterion where one light trap was set during two consecutive nights in peridomiciles in the transitions between the four seasons, and the environment was surveyed simultaneously. The relationships of phlebotomine assemblage structure and the most abundant species with seasonality and environmental variables were evaluated using a canonical correspondence analysis and generalized linear mixed models, respectively. A total of 5110 individuals were captured. Lutzomyia longipalpis (Lutz & Neiva, 1912) and Nyssomyia whitmani (Antunes & Coutinho, 1939) were the most abundant species captured in all samplings (98.3% of the total capture). The period of highest abundance of Lu. longipalpis was early autumn, and it was distributed in the most urbanized areas. Nyssomyia whitmani occupied mainly the less urbanized areas, showing peaks of abundance in early spring and summer. Other species were captured in low numbers and showed seasonal?spatial variations similar to those of Ny. whitmani . We confirmed Leishmania spp. vector persistence throughout the year in spatial patches of high abundance even during the less favorable season.     

Hydrogen-bond dynamics of water in presence of an amphiphile,tetramethylurea: signature of confinement-induced effects

Various experimental and simulation studies have suggested that the presence of amphiphilic molecules in aqueous solutions substantially perturbs the tetrahedral hydrogen-bond (H-bond) network of neat liquid water. Such structural perturbation is expected to impact H-bond lifetime of liquid water. Tetramethylurea (TMU) is an example of an amphiphile because it possesses both hydrophobic and hydrophilic moieties. Molecular dynamics simulations of (water+TMU) binary mixtures at various compositions have been performed in order to investigate the microscopic mechanism through which the amphiphiles influence the H-bond dynamics of liquid water at room temperature. Present simulations indicate lengthening of both water–water H-bond lifetime and H-bond structural relaxation time upon addition of TMU in aqueous solution. At the highest TMU mole fraction studied, H-bond lifetime and structural relaxation time are, respectively, ～4 and ～8 times longer than those in neat water. This is comparable with the slowing down of H-bond dynamics for water molecules confined in cyclodextrin cavities. Simulated relaxation profiles are multi-exponential in character at all mixture compositions, and simulated radial distribution functions suggest enhanced water–water and water–TMU interactions upon addition of TMU. No evidence for complete encapsulation of TMU by water H-bond network has been found.