Monte Carlo study of the effect of β2-microglobulin on the binding cleft of the HLA-A2 complex

Peptide recognition by class I products of the major histocompatibility complex requires association of the class I heavy chain with β₂-microglobulin. We present results of Monte Carlo simulations of the β-pleated sheet floor of the human class I MHC molecule, HLA-A2, with and without β₂-microglobulin. We find a significant effect of β₂-microglobulin on the side chains of residues near a region that would accommodate the C-terminus of a bound peptide. By modeling simultaneously each loop and its neighboring strand at either end of the class I cleft, we find that β₂-microglobulin restricts the conformational space of residues that are central to binding peptides. The effect is most pronounced for R97 and H114 and somewhat less important for Y99 and Y116, the latter forming strong hydrogen bonds with neighboring residues in the heavy chain itself.     

Enantiomerization of 2,2′-diisopropylbiphenyl during chiral inclusion gas chromatography: Determination of the rotational energy barrier by computer simulation of dynamic chromatographic elution profiles

By computer simulation of experimental dynamic gas chromatographic elution profiles, the rotational energy barrier ΔG⁼ of racemic 2,2′-diisopropylbiphenyl has been determined as 114.6–115.0 kJ/mol (75–100°C). These data are in good agreement with a value that was determined previously by measuring the racemization kinetics of an enriched sample. This indicates that there is no measurable catalytic or inhibitory effect of the stationary phase. © 1994 Wiley-Liss, Inc.     

The operational sex ratio influences choosiness in a pipefish

If more females than males are available for mating in the breedingpopulation (i.e., the operational sex ratio, OSR, is femalebiased), males can afford to be choosy. In the pipefish (Syngnathustyphle) females compete for males, who are choosy. In natureOSRs are typically female biased, but may occasionally be malebiased. In a series of experiments, males were allowed to choosebetween a large and a small female under a perceived excessof either males or females. Under female bias, males preferredthe large female: they spent more time close to her than tothe small female; they courted the large female sooner thanthe small; and they tended to copulate sooner and more oftenwith the large female. Under male bias all these differencesvanished and males mated at random with respect to female size.Males reproduced at a faster rate under male than under femalebias because they received more eggs in their brood pouches.Thus, males switched from maximizing mate quality (i.e., beingchoosy) to minimizing the risk of not reproducing (i.e., beingquick) as the OSR became male biased.     

Simulation of the light-induced oscillations of the membrane potential in Potamogeton leaf cells

Summary An attempt has been made to simulate the light-induced oscillations of the membrane potential of Potamogeton lucens leaf cells in relation to the apoplastic pH changes. Previously it was demonstrated that the membrane potential of these cells can be described in terms of proton movements only. It is hypothesized that the membrane potential is determined by an electrogenic H⁺-ATPase with a variable H⁺/ATP stoichiometry. The stoichiometry shifts from a value of two in the dark to a value of one in the light. Moreover, this H⁺ pump shows the characteristics of either a pump or a passive H⁺ conductance: the mode of operation of the H⁺ translocator is considered to be regulated by the external pH. The pump conductance is assumed to be dominant at low or neutral pH, while the passive H⁺ conductance becomes more significant at alkaline pH. The pH dependence of the transport characteristic is expressed by protonation reactions in the plasma membrane. The proposed model can account for most features of the light-induced oscillations but not for the absolute level of the membrane potential.This research was supported by the Foundation of Biophysics, part of the Dutch Organization for Scientific Research (NWO) ECOTRANS publication No. 34.     

A fractal model for the characterization of mycelial morphology

A new technique based on a fractal model has been developed for the quantification of the macroscopic morophology of mycelia. The morphological structuring is treated as a fractal object, and the fractal dimension, determined by an ultrasonic scattering procedure developed for the purpose, serves as a quantitative morphological index. Experimental observations reported earlier and simulations of mycelial growth, carried out using a probabilistic-geometric growth model developed for the purpose, both validate the applicability of the fractal model. In experiments with three different species, the fractal dimensions of pelletous structures were found to be in the range 1.45-2.0 and those of filamentous structures were in the range 1.9-2.7, with values around 2.0 representing mixed morphologies. Fractal dimensions calculated from simulated mycelia are in rough agreement with these ranges. The fractal dimension is also found to be relatively insensitive to the biomass concentration, as seen by dilution of the original broths. The relation between morphology and filtration properties of the broths has also been studied. The fractal dimension shows a strong correlation with the index of cake compressibility and with the Kozeny constant, two filtration parameters that are known to be morphology dependent. This technique could thus be used to develop correlations between the morphology, represented by the fractal dimension, and important morphology-dependent process variables. (c) 1993 John Wiley & Sons, Inc.     

Screening and molecular dynamics simulation of compounds inhibiting MurB enzyme of drug-resistant Mycobacterium tuberculosis: An in-silico approach

Mycobacterium tuberculosis (MTB) is becoming more and more resistant to drugs and it is a common problem, making current antimicrobials ineffective and highlighting the need for new TB drugs. One of the promising targets for treating MTB is MurB enzymes. This study aimed to identify potential inhibitors of MurB enzymes in M. tuberculosis, as drug resistance among MTB is a significant problem. Attempts are being made to conduct a virtual screening of 30,417 compounds, and thirty-two compounds were chosen for further analysis based on their binding conformations. The selected compounds were assessed for their drug-likeness, pharmacokinetics, and physiochemical characteristics, and seven compounds with binding energy lower than flavin (FAD) were identified. Further, molecular dynamics simulation analysis of these seven compounds found that four of them, namely DB12983, DB15688, ZINC084726167, and ZINC254071113 formed stable complexes with the MurB binding site, exhibiting promising inhibitory activity. These compounds have not been mentioned in any other study, indicating their novelty. The study suggests that these four compounds could be promising candidates for treating MTB, but their effectiveness needs to be validated through in vitro and in vivo experiments. Overall, the findings of this study provide new insight into potential drug targets and candidates for combating drug-resistant MTB.     

Defining null expectations for animal site fidelity

Site fidelity—the tendency to return to previously visited locations—is widespread across taxa. Returns may be driven by several mechanisms, including memory, habitat selection, or chance; however, pattern-based definitions group different generating mechanisms under the same label of ‘site fidelity’, often assuming memory as the main driver. We propose an operational definition of site fidelity as patterns of return that deviate from a null expectation derived from a memory-free movement model. First, using agent-based simulations, we show that without memory, intrinsic movement characteristics and extrinsic landscape characteristics are key determinants of return patterns and that even random movements may generate substantial probabilities of return. Second, we illustrate how to implement our framework empirically to establish ecologically meaningful, system-specific null expectations for site fidelity. Our approach provides a conceptual and operational framework to test hypotheses on site fidelity across systems and scales.     

Mechanisms of group-hunting in vertebrates

Group-hunting is ubiquitous across animal taxa and has received considerable attention in the context of its functions. By contrast much less is known about the mechanisms by which grouping predators hunt their prey. This is primarily due to a lack of experimental manipulation alongside logistical difficulties quantifying the behaviour of multiple predators at high spatiotemporal resolution as they search, select, and capture wild prey. However, the use of new remote-sensing technologies and a broadening of the focal taxa beyond apex predators provides researchers with a great opportunity to discern accurately how multiple predators hunt together and not just whether doing so provides hunters with a per capita benefit. We incorporate many ideas from collective behaviour and locomotion throughout this review to make testable predictions for future researchers and pay particular attention to the role that computer simulation can play in a feedback loop with empirical data collection. Our review of the literature showed that the breadth of predator:prey size ratios among the taxa that can be considered to hunt as a group is very large (<10⁰ to >10²). We therefore synthesised the literature with respect to these predator:prey ratios and found that they promoted different hunting mechanisms. Additionally, these different hunting mechanisms are also related to particular stages of the hunt (search, selection, capture) and thus we structure our review in accordance with these two factors (stage of the hunt and predator:prey size ratio). We identify several novel group-hunting mechanisms which are largely untested, particularly under field conditions, and we also highlight a range of potential study organisms that are amenable to experimental testing of these mechanisms in connection with tracking technology. We believe that a combination of new hypotheses, study systems and methodological approaches should help push the field of group-hunting in new directions.     

N-glycosylation induced changes in tau protein dynamics reveal its role in tau misfolding and aggregation: A microsecond long molecular dynamics study

Various posttranslational modifications like hyperphosphorylation, O-GlcNAcylation, and acetylation have been attributed to induce the abnormal folding in tau protein. Recent in vitro studies revealed the possible involvement of N-glycosylation of tau protein in the abnormal folding and tau aggregation. Hence, in this study, we performed a microsecond long all atom molecular dynamics simulation to gain insights into the effects of N-glycosylation on Asn-359 residue which forms part of the microtubule binding region. Trajectory analysis of the stimulations coupled with essential dynamics and free energy landscape analysis suggested that tau, in its N-glycosylated form tends to exist in a largely folded conformation having high beta sheet propensity as compared to unmodified tau which exists in a large extended form with very less beta sheet propensity. Residue interaction network analysis of the lowest energy conformations further revealed that Phe378 and Lys353 are the functionally important residues in the peptide which helped in initiating the folding process and Phe378, Lys347, and Lys370 helped to maintain the stability of the protein in the folded state.