Effects of heterogeneity and cooperativity on the forms of binding curves for multivalent ligands

An exploratory investigation is made of the binding behavior that is likely to be encountered with multivalent ligands under circumstances where a single intrinsic binding constant does not suffice to describe all acceptor-ligand interactions. Numerical simulations of theoretical binding behavior have established that current criteria for recognizing heterogeneity and cooperativity of acceptor sites on the basis of the deviation of the binding curve from rectangular hyperbolic form for univalent ligands also apply to the interpretation of the corresponding binding curves for multivalent ligands. However, for systems in which the source of the departure from equivalence and independence of binding sites resides in the ligand, these criteria are reversed. On the basis of these observations a case is then made for attributing results of an experimental binding study of the interaction between pyruvate kinase and muscle myofibrils to positive cooperativity of enzyme sites rather than to heterogeneity or negative cooperativity of the myofibrillar sites.     

Interaction coefficients in the Lake Shira algal-bacterial community

A new method is proposed to evaluate the interaction coefficients in microbial communities interacting due to physical-chemical environmental factors. This method differs from the classical one suggested by E.P.Odum. Redefinition of the interaction coefficients allows the evaluation of the experimental (actual) and theoretical values of the coefficients for the hypothetical interaction layout. The interaction layout is considered to be a set of factors, the values of their transformation ratios and the form of dependence of a population's specific growth rate on these factors. A comparison of theoretical and experimental values of interaction coefficients enables us to assess the adequacy of the hypothetical interaction scheme in the microbial communities. The aim of the work is to test the suggested method on a natural algal-bacterial community of Shira Lake (Khakasia, Russia), which has been the object of detailed and concerted limnological studies and for which detailed data are available. Feedback coefficients of phyto- and bacterioplankton and the coefficients of influence of phytoplankton on bacterioplankton have been defined. Dominance of negative experimental IC values has been experimentally shown, which is indicative of the negative feedback in bacterio- and phytoplankton links of Shira Lake and of negative interpopulation (phytoplankton on bacterioplankton) interactions. The considerable differences observed between the experimental and theoretical coefficients indicates inadequacy of the assumed interaction layout of the community under study. Further investigations are needed to provide a precise sketch of the interactions.     

Extent of enthalpy-entropy compensation in protein-ligand interactions

The extent of enthalpy-entropy compensation in protein-ligand interactions has long been disputed because negatively correlated enthalpy (ΔH) and entropy (TΔS) changes can arise from constraints imposed by experimental and analytical procedures as well as through a physical compensation mechanism. To distinguish these possibilities, we have created quantitative models of the effects of experimental constraints on isothermal titration calorimetry (ITC) measurements. These constraints are found to obscure any compensation that may be present in common data representations and regression analyses (e.g., in ΔH vs. -TΔS plots). However, transforming the thermodynamic data into ΔΔ-plots of the differences between all pairs of ligands that bind each protein diminishes the influence of experimental constraints and representational bias. Statistical analysis of data from 32 diverse proteins shows a significant and widespread tendency to compensation. ΔΔH versus ΔΔG plots reveal a wide variation in the extent of compensation for different ligand modifications. While strong compensation (ΔΔH and -TΔΔS opposed and differing by < 20% in magnitude) is observed for 22% of modifications (twice that expected without compensation), 15% of modifications result in reinforcement (ΔΔH and -TΔΔS of the same sign). Because both enthalpy and entropy changes arise from changes to the distribution of energy states on binding, there is a general theoretical expectation of compensated behavior. However, prior theoretical studies have focussed on explaining a stronger tendency to compensation than actually found here. These results, showing strong but imperfect compensation, will act as a benchmark for future theoretical models of the thermodynamic consequences of ligand modification.     

Interaction between sodium n-undecyl sulfate and insulin

The binding of sodium n-undecyl sulfate with bovine insulin was studied at pH 3.2 and 10 by equilibrium dialysis at 25°C. The binding data have been used to determine the Gibbs energies of interaction using the theoretical model of the Wyman binding potential. The curves of Gibbs energies as a function of the number of bound ligands ( ) tend to limiting values of around −14 kJ mol⁻¹ at high values of . The enthalpies of in interaction have been measured directly by microcalorimetry showing an increase of exothermicity at lower pH. The results have been compared with similar data for the interaction of anionic surfactants with insulin.     

Frontiers in population ecology of microtine rodents: A pluralistic approach to the study of population ecology

Current challenges for the study of population ecology of microtine rodents are reviewed. Comparisons with other taxonomic groups (other mammals, birds and insects) are given throughout. A major challenge is to link patterns and processes (i.e. mechanisms) better than is the case today. Other major challenges include the furthering of our understanding of the interaction between deterministic and stochastic processes, and as part thereof, the interaction between density-dependent and density-independent processes. The applicability of comparative studies on populations exhibiting different temporal dynamical patterns is, in this connection, emphasized. Understanding spatiotemporal dynamical patterns is another major challenge, not the least from a methodological point of view. Long-term and large-scale ecological data on population dynamics (in space and time) are critical for this purpose. Looking for consistency between hypothesized mechanisms and observed patterns is emphasized as a good platform for further empirical and theoretical work. The intellectual feedback process between different approaches to the study of microtine population ecology (observational studies, experimental manipulative studies, statistical modeling and mathematical modeling) are discussed. We recommend a pluralistic approach (involving both observational and experimental as well as theoretical studies) to the study of small rodent ecology.     

Computational estimation of specific side chain interaction energies in alpha helices

We have used a structure energy-based computer program developed for protein design, Perla, to provide theoretical estimates of all specific side chain-side chain interaction energies occurring in alpha helices. The computed side chain-side chain interaction energies were used as substitutes for the corresponding values used by the helix/coil transition algorithm, AGADIR. Predictions of peptide helical contents were nearly as successful as those obtained with the originally calibrated set of parameters; a correlation to experimentally observed alpha-helical populations of 0.91 proved that our theoretical estimates are reasonably correct for amino acid pairs that are frequent in our database of peptides. Furthermore, we have determined experimentally the previously uncharacterized interaction energies for Lys-Ile, Thr-Ile, and Phe-Ile amino acid pairs at i,i + 4 positions. The experimental values compare favorably with the computed theoretical estimates. Importantly, the computed values for Thr-Ile and Phe-Ile interactions are better than the energies based on chemical similarity, whereas for Lys-Ile they are similar. Thus, computational techniques can be used to provide precise energies for amino acid pairwise interactions, a fact that supports the development of structure energy-based computational tools for structure predictions and sequence design.     

Disentangling the effect of hybrid interactions and of the constant effort hypothesis on ecological community stability

In the last years, a remarkable theoretical effort has been made in order to understand the relation between stability and complexity in ecological communities. Yet, what maintains species diversity in real ecological communities is still an open question. The non‐random structures of ecological interaction networks have been recognized as one key ingredient impacting the maximum number of coexisting species within the ecological community. However most of the earlier theoretical studies have considered communities with only one interaction type (either antagonistic, competitive or mutualistic). Recently, it has been proposed that multiple interaction types might stabilize ecosystems and that, in this hybrid case, increasing complexity increases stability. Here we show that these results depend on ad hoc hypothesis that the authors used in their model and we highlight the need to disentangle the role of multiple interaction types and constant interaction effort allocation on community stability. Indeed, we find that mixing of mutualistic and predator–prey interaction types does not stabilize the community dynamics and we demonstrate that a positive correlation between complexity and stability is observed only if a constant effort allocation is imposed in the ecological interactions. Synthesis In recent years a sparkling research has been devoted to the search of new theoretical mechanisms to explain way ecosystems may persist despite their complexity. Here we show that, contrary to what recently suggested (Mougi et al. 2012), the mismatch between theoretical results and empirical evidences on the stability of ecological community is still there also for communities with both mutualistic and antagonistic interactions, and the ‘complexity‐stability’ paradox is still alive. Indeed, we demonstrate that their results arise as an artifact of the peculiar rescaling of the interaction strengths they imposed. Our study suggests that further theoretical studies and experimental evidences are still needed to better understand the role of interaction strengths in real ecological communities.     

捕食者-猎物关系的理论和应用研究

捕食者和猎物相互关系的研究,长期以来一直是动物生态学研究的中心课题之一。这种研究可区分为3种类型:第一是理论研究,即组建各种数学模型以便模拟捕食者和猎物间的相互关系;第二是实验种群研究,通常是在实验室内选用原生动物和节肢动物实验种群对捕食一猎物间的动态关系进行观察,并将观察结果与理论模型进行比较;第三是在田间对自然种群中的捕食者-猎物关系进行研究,并利用从理论研究和实验种群研究中所总结出来的各种基本原理对观察资料进行分析。在应用生态学领域中,常常靠引进新的更加有效的天敌来控制各种害虫。这些实际工作有些已获得成功,也有不少未取得预期效果,不管成功与否,它们都可被看作是对捕食者-猎物关系所进行的田间实验.     

A theoretical model simulating the anomalous concentration dependence of the equilibrium thermal unfolding curve of noncrosslinked tropomyosin

Thermal unfolding curves of tropomyosin have so far been fit only semi-quantitatively by the statistical-mechanical theory of the helix-coil transition. The calculated values of helix content are a bit too small for the most dilute solutions and a bit too large for the most concentrated ones. The theory, as hitherto used, assumes a uniform helix-helix interaction, whereas evidence from studies on molecular segments suggests otherwise. A theoretical model incorporating such non-uniformity in helix-helix interaction is used to produce simulated thermal unfolding curves. These simulated curves, when fit to the theory using the assumption of uniformity, reveal precisely the same discrepancies seen with the experimental data. We conclude that non-uniformity in helix-helix interaction along the tropomyosin molecule is responsible for the small discrepancy between experimental data and the uniform-model theory previously employed.     

昆虫种间表观竞争研究进展

表观竞争是资源竞争以外的一种新型的种间关系,是指由共同享有的自然天敌中介的、物种之间在种群数量上表现出明显负效应的现象。物种之间的表观竞争被认为和资源竞争具有同等的重要性,尤其是对植食性昆虫来说更为重要。近十年来关于昆虫表观竞争的理论和实验研究进展迅速,已成为昆虫生态学研究中的一个新的生长点。本文从表观竞争的定义、实验研究实例、理论模型、作用机制及共存机制等方面,对近些年来关于昆虫表观竞争研究的进展进行了概括和总结,并对表观竞争理论在害虫防治中的应用前景进行了展望。     

Dual Logic and Cerebral Coordinates for Reciprocal Interaction in Eye Contact

In order to scientifically study the human brain’s response to face-to-face social interaction, the scientific method itself needs to be reconsidered so that both quantitative observation and symbolic reasoning can be adapted to the situation where the observer is also observed. In light of the recent development of dyadic fMRI which can directly observe dyadic brain interacting in one MRI scanner, this paper aims to establish a new form of logic, dual logic, which provides a theoretical platform for deductive reasoning in a complementary dual system with emergence mechanism. Applying the dual logic in the dfMRI experimental design and data analysis, the exogenous and endogenous dual systems in the BOLD responses can be identified; the non-reciprocal responses in the dual system can be suppressed; a cerebral coordinate for reciprocal interaction can be generated. Elucidated by dual logic deductions, the cerebral coordinate for reciprocal interaction suggests: the exogenous and endogenous systems consist of the empathy network and the mentalization network respectively; the default-mode network emerges from the resting state to activation in the endogenous system during reciprocal interaction; the cingulate plays an essential role in the emergence from the exogenous system to the endogenous system. Overall, the dual logic deductions are supported by the dfMRI experimental results and are consistent with current literature. Both the theoretical framework and experimental method set the stage to formally apply the scientific method in studying complex social interaction.     

Brownian dynamics simulation of protein solutions: structural and dynamical properties

The study of solutions of biomacromolecules provides an important basis for understanding the behavior of many fundamental cellular processes, such as protein folding, self-assembly, biochemical reactions, and signal transduction. Here, we describe a Brownian dynamics simulation procedure and its validation for the study of the dynamic and structural properties of protein solutions. In the model used, the proteins are treated as atomically detailed rigid bodies moving in a continuum solvent. The protein-protein interaction forces are described by the sum of electrostatic interaction, electrostatic desolvation, nonpolar desolvation, and soft-core repulsion terms. The linearized Poisson-Boltzmann equation is solved to compute electrostatic terms. Simulations of homogeneous solutions of three different proteins with varying concentrations, pH, and ionic strength were performed. The results were compared to experimental data and theoretical values in terms of long-time self-diffusion coefficients, second virial coefficients, and structure factors. The results agree with the experimental trends and, in many cases, experimental values are reproduced quantitatively. There are no parameters specific to certain protein types in the interaction model, and hence the model should be applicable to the simulation of the behavior of mixtures of macromolecules in cell-like crowded environments.     

Mapping of ligand binding sites of the cholecystokinin-B/gastrin receptor with lipo-gastrin peptides and molecular modeling

Double-tailed lipo-tetragastrin derivatives of increasing fatty acid chain length were used to identify the minimum size of the fatty acid moieties (≥C10) that restricts the access to the CCK-B/gastrin (CCK: cholecystokinin) receptor via a membrane-bound pathway. Then dimyristoyl-mercaptoglycerol/maleoyl-gastrin adducts of increasing peptide chain length were synthesized to define the minimal peptide size required for receptor binding affinities comparable to those of underivatized gastrin peptides despite anchorage of the lipid tails in the membrane bilayer. The experimental results indicated that most of the little-gastrin sequence, i.e., 2–17, is needed for optimal interaction of the molecule with the binding cleft of the receptor. From these data experimentally based restraints could be derived for docking of lipo-gastrin onto a CCK-B/gastrin receptor model applying molecular dynamics simulations and energy minimizations. In the receptor-bound state some of the secondary structure elements of gastrin as determined by nmr analysis of gastrin-peptides in low dielectric constant media are retained. The N-terminal gastrin portion interacts in a more or less extended conformation with the receptor surface, and upon a sharp kink at the Ala-Tyr dipeptide portion the C-terminal pentapeptide amide part inserts deeply into the helix bundle. Besides Arg-57 on top of helix 1 of the receptor, for which no potential interaction with the ligand could be detected, the other amino acid residues identified by mutagenesis studies as involved in gastrin recognition were found to interact with the C-terminal portion of gastrin. Even taking into account the strong limitations of such a model system, it represents an interesting tool for rationalizing the experimental results of the extensive structure-function studies performed previously on gastrin and to delineate more precisely the putative ligand binding site on the extracellular face of the receptor. © 1997 John Wiley & Sons, Inc. Biopoly 41: 799–817, 1997     

Poisson-Boltzmann analysis of the lambda repressor-operator interaction.

A theoretical study of the ion atmosphere contribution to the binding free energy of the lambda repressor-operator complex is presented. The finite-difference form of the Poisson-Boltzmann equation was solved to calculate the electrostatic interaction energy of the amino-terminal domain of the lambda repressor with a 9 or 45 base pair oligonucleotide. Calculations were performed at various distances between repressor and operator as well as at different salt concentrations to determine ion atmosphere contributions to the total electrostatic interaction. Details in the distribution of charges on DNA and protein atoms had a strong influence on the calculated total interaction energies. In contrast, the calculated salt contributions are relatively insensitive to changes in the details of the charge distribution. The results indicate that the ion atmosphere contribution favors association at all protein-DNA distances studied. The theoretical number of ions released upon repressor-operator binding appears to be in reasonable agreement with experimental data.     

Polyelectrolyte theory and chromatin-DNA quaternary structure: Role of ionic strength and Hl histone

Under the assumptions outlined in this paper and those of Manning's theory of polyelectrolyte screening the electrostatic interaction of histone 1 and DNA is examined and shown to lead to spontaneous bending of DNA. Critical variables for this bending are the ionic strength, the length of DNA interacting with each histone 1 molecule, and the fraction of DNA phosphate charges neutralized by the histone 1 molecule. This interaction is postulated as accounting for the observed folding of polynucleosomes into the “solenoid” regular structure. Wherever possible comparison is made between theoretical predictions and available experimental results. Finally, biological implications are briefly discussed.     

Energetic contributions of amino acid residues and its cross-talk to delineate ligand-binding mechanism

Receptor-based QSAR approaches can enumerate the energetic contributions of amino acid residues toward ligand binding only when experimental binding affinity is associated. The structural data of protein-ligand complexes are witnessing a tremendous growth in the Protein Data Bank deposited with a few entries on binding affinity. We present here a new approach to compute the E nergetic CONT ributions of A mino acid residues and its possible C ross-T alk (ECONTACT) to study ligand binding using per-residue energy decomposition, molecular dynamics simulations and rescoring method without the need for experimental binding affinity. This approach recognizes potential cross-talks among amino acid residues imparting a nonadditive effect to the binding affinity with evidence of correlative motions in the dynamics simulations. The protein-ligand interaction energies deduced from multiple structures are decomposed into per-residue energy terms, which are employed as variables to principal component analysis and generated cross-terms. Out of 16 cross-talks derived from eight datasets of protein-ligand systems, the ECONTACT approach is able to associate 10 potential cross-talks with site-directed mutagenesis, free energy, and dynamics simulations data strongly. We modeled these key determinants of ligand binding using joint probability density function (jPDF) to identify cross-talks in protein structures. The top two cross-talks identified by ECONTACT approach corroborated with the experimental findings. Furthermore, virtual screening exercise using ECONTACT models better discriminated known inhibitors from decoy molecules. This approach proposes the jPDF metric to estimate the probability of observing cross-talks in any protein-ligand complex. The source code and related resources to perform ECONTACT modeling is available freely at https://www.gujaratuniversity.ac.in/econtact /.     

Integrating theory into disturbance interaction experiments to better inform ecosystem management

Managing multiple, interacting disturbances is a key challenge to biodiversity conservation, and one that will only increase as global change drivers continue to alter disturbance regimes. Theoretical studies have highlighted the importance of a mechanistic understanding of stressor interactions for improving the prediction and management of interactive effects. However, many conservation studies are not designed or interpreted in the context of theory and instead focus on case‐specific management questions. This is a problem as it means that few studies test the relationships highlighted in theoretical models as being important for ecological management. We explore the extent of this problem among studies of interacting disturbances by reviewing recent experimental studies of the interaction between fire and grazing in terrestrial ecosystems. Interactions between fire and grazing can occur via a number of pathways; one disturbance can modify the other's likelihood, intensity or spatial distribution, or one disturbance can alter the other's impacts on individual organisms. The strength of such interactions will vary depending on disturbance attributes (e.g. size or intensity), and this variation is likely to be nonlinear. We show that few experiments testing fire–grazing interactions are able to identify the mechanistic pathway driving an observed interaction, and most are unable to detect nonlinear effects. We demonstrate how these limitations compromise the ability of experimental studies to effectively inform ecological management. We propose a series of adjustments to the design of disturbance interaction experiments that would enable tests of key theoretical pathways and provide the deeper ecological understanding necessary for effective management. Such considerations are relevant to studies of a broad range of ecological interactions and are critical to informing the management of disturbance regimes in the context of accelerating global change.     

A QM protein–ligand investigation of antipsychotic drugs with the dopamine D2 Receptor (D2R)

The dopamine D2 Receptor (D2R) is a member of the G-Protein-Coupled Receptor family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson’s disease. D2R is the target protein of the commonly used antipsychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone, and quetiapine. Due to their significant side effects and non-selective profiles, the discovery of novel drugs has become a challenge for researchers working in this field. Recently, our group has focused on the interactions of these drug molecules in the active site of the D2R using different in silico approaches. We here compare the performances of different approaches in estimating the drug binding affinities using quantum chemical approaches. Conformations of drug molecules (ligands) at the binding site of the D2R taken from the preliminary docking studies and molecular dynamics simulations were used to generate protein–ligand interaction models. In a first approach, the BSSE-corrected interaction energies of the ligands with the most critical amino acid Asp114 and with the other amino acids closest to ligands in the binding cavity were calculated separately by density functional theory method in implicit water environment at the M06-2X/6-31 g(d,p) level of the theory. In a second approach, ligand binding affinities were calculated by taking into consideration not only the interaction energies but also deformation and desolvation energies of ligands with surrounding amino acid residues, in a radius of 5 Å of the protein-bound ligand. The quantum mechanically obtained results were compared with the experimentally obtained binding affinity values. We concluded that although H-bond interactions of ligands with Asp114 are the most dominant interaction in the binding site, if van der Waals and steric interactions of ligands which have cumulative effect on the ligand binding are not included in the calculations, the interaction energies are overestimated.