M8R tropomyosin mutation disrupts actin binding and filament regulation: The beginning affects the middle and end

Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin''s reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T''s N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM.     

Survival synchronicity in two avian insectivore communities

Climate change is forecast to increase climatic variability, in particular the occurrence of extreme events. Consequently, it is imperative to understand how climatic variation influences the dynamics of communities. We investigated synchronicity in survival in response to climatic variation among bird communities occupying habitats that differed in climatic seasonality: a more seasonal wetland and a less seasonal fynbos shrubland in South Africa. We predicted higher synchronicity at the wetland than at the shrubland because there was more potential for weather to induce variation in survival at this climatically more variable site. We estimated survival from ringing data for four wetland species and three fynbos species in hierarchical models with an asynchronous (species-specific) variance component and a synchronous (common) variance component. Comparing models including and excluding a climatic covariate enabled us to estimate the effect of climatic variation as a synchronizing and desynchronizing agent on survival. As hypothesized, synchronicity in survival was substantially greater at the more seasonal wetland than at the climatically more stable fynbos site: 0.50 (95% credible interval 0.01–1.92 on the logit scale) and 0.03 (0.00001–0.19), respectively. Similarly, asynchronicity in survival was greater for wetland species than for fynbos species. However, we found no clear evidence that weather affected survival. We provide the first survival estimates of several African endemic birds and the first estimates of synchronicity and asynchronicity in survival of communities outside the strongly seasonal northern temperate zone. Our results suggest that the relative magnitude of synchronicity and asynchronicity varies among communities and support the idea that environmental variability induces synchronicity.     

Cholesterol sensing by CD81 is important for hepatitis C virus entry

CD81 plays a central role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the large extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol-sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81–cholesterol association but had disparate effects on HCV entry, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified a potential allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol-unbound) or closed (cholesterol-bound) conformation. The open mutant of CD81 exhibited reduced HCV receptor activity, whereas the closed mutant enhanced activity. These data are consistent with cholesterol sensing switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81–partner protein networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry, and CD81''s function as a molecular scaffold; these insights are relevant to CD81''s varied roles in both health and disease.     

The complex fluctuations of probabilistic Boolean networks

Probabilistic Boolean networks (PBNs) are extensions of Boolean networks (BNs), and both have been widely used to model biological systems. In this paper, we study the long-range correlations of PBNs based on their corresponding Markov chains. PBN states are quantified by the deviation of their steady-state distributions. The results demonstrate that, compared with BNs, PBNs can exhibit these dynamics over a wider and higher noise range. In addition, the constituent BNs significantly impact the generation of 1/f dynamics of PBNs, and PBNs with homogeneous steady-state distributions tend to sustain the 1/f dynamics over a wider noise range.     

Invasion of cooperators in lattice populations: Linear and non-linear public good games

A generalized version of the N-person volunteer's dilemma (NVD) Game has been suggested recently for illustrating the problem of N-person social dilemmas. Using standard replicator dynamics it can be shown that coexistence of cooperators and defectors is typical in this model. However, the question of how a rare mutant cooperator could invade a population of defectors is still open.     

Exploring the concept of interaction computing through the discrete algebraic analysis of the Belousov–Zhabotinsky reaction

Interaction computing (IC) aims to map the properties of integrable low-dimensional non-linear dynamical systems to the discrete domain of finite-state automata in an attempt to reproduce in software the self-organizing and dynamically stable properties of sub-cellular biochemical systems. As the work reported in this paper is still at the early stages of theory development it focuses on the analysis of a particularly simple chemical oscillator, the Belousov–Zhabotinsky (BZ) reaction. After retracing the rationale for IC developed over the past several years from the physical, biological, mathematical, and computer science points of view, the paper presents an elementary discussion of the Krohn–Rhodes decomposition of finite-state automata, including the holonomy decomposition of a simple automaton, and of its interpretation as an abstract positional number system. The method is then applied to the analysis of the algebraic properties of discrete finite-state automata derived from a simplified Petri net model of the BZ reaction. In the simplest possible and symmetrical case the corresponding automaton is, not surprisingly, found to contain exclusively cyclic groups. In a second, asymmetrical case, the decomposition is much more complex and includes five different simple non-abelian groups whose potential relevance arises from their ability to encode functionally complete algebras. The possible computational relevance of these findings is discussed and possible conclusions are drawn.     

The impact of high hydrostatic pressure on structure and dynamics of β-lactoglobulin

Methods

Combining small-angle X-ray and neutron scattering measurements with inelastic neutron scattering experiments, we investigated the impact of high hydrostatic pressure on the structure and dynamics of β-lactoglobulin (βLG) in aqueous solution.

Background

βLG is a relatively small protein, which is predominantly dimeric in physiological conditions, but dissociates to monomer below about pH 3.

Results

High-pressure structural results show that the dimer–monomer equilibrium, as well as the protein–protein interactions, are only slightly perturbed by pressure, and βLG unfolding is observed above a threshold value of 3000 bar. In the same range of pressure, dynamical results put in evidence a slowing down of the protein dynamics in the picosecond timescale and a loss of rigidity of the βLG structure. This dynamical behavior can be related to the onset of unfolding processes, probably promoted from water penetration in the hydrophobic cavity.

General significance

Results suggest that density and compressibility of water molecules in contact with the protein are key parameters to regulate the protein flexibility.     

Effects of climate warming on host–parasitoid interactions

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Comparison of dynamics of wildtype and V94M human UDP-galactose 4-epimerase—A computational perspective on severe epimerase-deficiency galactosemia

UDP-galactose 4′-epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose, an important step in galactose catabolism. Type III galactosemia, an inherited metabolic disease, is associated with mutations in human GALE. The V94M mutation has been associated with a very severe form of type III galactosemia. While a variety of structural and biochemical studies have been reported that elucidate differences between the wildtype and this mutant form of human GALE, little is known about the dynamics of the protein and how mutations influence structure and function. We performed molecular dynamics simulations on the wildtype and V94M enzyme in different states of substrate and cofactor binding. In the mutant, the average distance between the substrate and both a key catalytic residue (Tyr157) and the enzyme-bound NAD⁺ cofactor and the active site dynamics are altered making substrate binding slightly less stable. However, overall stability or dynamics of the protein is not altered. This is consistent with experimental findings that the impact is largely on the turnover number (k_cat), with less substantial effects on K_m. Active site fluctuations were found to be correlated in enzyme with substrate bound to just one of the subunits in the homodimer suggesting inter-subunit communication. Greater active site loop mobility in human GALE compared to the equivalent loop in Escherichia coli GALE explains why the former can catalyze the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine while the bacterial enzyme cannot. This work illuminates molecular mechanisms of disease and may inform the design of small molecule therapies for type III galactosemia.