Designed helical peptides inhibit an intramembrane protease

gamma-Secretase cleaves the transmembrane domain of the amyloid precursor protein, a process implicated in the pathogenesis of Alzheimer's disease, and this enzyme is a founding member of an emerging class of intramembrane proteases. Modeling and mutagenesis suggest a helical conformation for the substrate transmembrane domain upon initial interaction with the protease. Moreover, biochemical evidence supports the presence of an initial docking site for substrate on gamma-secretase that is distinct from the active site, a property predicted to be generally true of intramembrane proteases. Here we show that short peptides designed to adopt a helical conformation in solution are inhibitors of gamma-secretase in both cells and enzyme preparations. Helical peptides with all d-amino acids are the most potent inhibitors and represent potential therapeutic leads. Subtle modifications that disrupt helicity also substantially reduce potency, suggesting that this conformation is critical for effective inhibition. Fluorescence lifetime imaging in intact cells demonstrates that helical peptides disrupt binding between substrate and protease, whereas an active site-directed inhibitor does not. These findings are consistent with helical peptides interacting with the initial substrate docking site of gamma-secretase, suggesting a general strategy for the development of potent and specific inhibitors of intramembrane proteases.     

Fractal landscapes in biological systems: long-range correlations in DNA and interbeat heart intervals

Here we discuss recent advances in applying ideas of fractals and disordered systems to two topics of biological interest, both topics having common the appearance of scale-free phenomena, i.e., correlations that have no characteristic length scale, typically exhibited by physical systems near a critical point and dynamical systems far from equilibrium. (i) DNA nucleotide sequences have traditionally been analyzed using models which incorporate the possibility of short-range nucleotide correlations. We found, instead, a remarkably long-range power law correlation. We found such long-range correlations in intron-containing genes and in non-transcribed regulatory DNA sequences as well as intragenomic DNA, but not in cDNA sequences or intron-less genes. We also found that the myosin heavy chain family gene evolution increases the fractal complexity of the DNA landscapes, consistent with the intron-late hypothesis of gene evolution. (ii) The healthy heartbeat is traditionally thought to be regulated according to the classical principle of homeostasis, whereby physiologic systems operate to reduce variability and achieve an equilibrium-like state. We found, however, that under normal conditions, beat-to-beat fluctuations in heart rate display long-range power law correlations.     

Computing the function GM(υ)

Tables are presented on the function G_M() which describes head waves or waves propagating near a concave surface.Translated from Zapiski Nauchnykh Seminarov Leningradskogo Otdeleniya Matematicheskogo Instituta im. V. A. Steklova AN SSSR, Vol. 51, pp. 85–92, 1975.     

Liquid polyamorphism: Possible relation to the anomalous behaviour of water

We present evidence from experiments and computer simulations supporting the hypothesis that water displays polyamorphism, i.e., water separates into two distinct liquid phases. This concept of a new liquid-liquid phase transition is finding application to other liquids as well as water, such as silicon and silica. Specifically, we investigate, the relation between changes in dynamic and thermodynamic anomalies arising from the presence of the liquid-liquid critical point in (i) Two models of water, TIP5P and ST2, which display a first order liquid-liquid phase transition at low temperatures; (ii) the Jagla model, a spherically symmetric two-scale potential known to possess a liquid-liquid critical point, in which the competition between two liquid structures is generated by repulsive and attractive ramp interactions; and (iii) A Hamiltonian model of water where the idea of two length/energy scales is built in. This model also displays a first order liquid-liquid phase transition at low temperatures besides the first order liquid-gas phase transition at high temperatures. We find a correlation between the dynamic fragility crossover and the locus of specific heat maxima C_P^max (“Widom line”) emanating from the critical point. Our findings are consistent with a possible relation between the previously hypothesised liquid-liquid phase transition and the transition in the dynamics recently observed in neutron scattering experiments on confined water. More generally, we argue that this connection between C_P^max and the dynamic crossover is not limited to the case of water, a hydrogen bonded network liquid, but is a more general feature of crossing the Widom line, an extension of the first-order coexistence line in the supercritical region. Dedicated to Armin Bunde on the occasion of his 60th birthday.     

Quasicrystals in a monodisperse system

We investigate the formation of a two-dimensional quasicrystal in a monodisperse system, using molecular dynamics simulations of hard-sphere particles interacting via a two-dimensional square-well potential. We find that more than one stable crystalline phase can form for certain values of the square-well parameters. Quenching the liquid phase at a very low temperature, we obtain an amorphous phase. By heating this amorphous phase, we obtain a quasicrystalline structure with fivefold symmetry. From estimations of the Helmholtz potentials of the stable crystalline phases and of the quasicrystal, we conclude that the observed quasicrystal phase can be the stable phase in a specific range of temperatures.     

Anomalous transport in scale-free networks

To study transport properties of scale-free and Erdos-Rényi networks, we analyze the conductance G between two arbitrarily chosen nodes of random scale-free networks with degree distribution P(k)-k(-lambda) in which all links have unit resistance. We predict a broad range of values of G, with a power-law tail distribution phi(SF)(G)-G(-g(G)), where g(G)=2lambda-1, and confirm our predictions by simulations. The power-law tail in phi(SF)(G) leads to large values of G, signaling better transport in scale-free networks compared to Erdos-Rényi networks where the tail of the conductivity distribution decays exponentially. Based on a simple physical "transport backbone" picture we show that the conductances of scale-free and Erdos-Rényi networks are well approximated by ck(A)k(B)/(k(A)+k(B)) for any pair of nodes A and B with degrees k(A) and k(B), where c emerges as the main parameter characterizing network transport.     

Structural order for one-scale and two-scale potentials

We perform molecular dynamics simulations to investigate the relationship between structural order and waterlike dynamic and thermodynamic anomalies in spherically symmetric potentials having either one or two characteristic length scales. Structural order is characterized by translational and orientational order parameters. We find that (i) dynamic and thermodynamic anomalies exist for both one-scale and two-scale ramp potentials, and (ii) waterlike structural order anomalies exist only for the two-scale ramp potential. Our findings suggest that the waterlike relationship between structural order and anomalies is related to the presence of two different length scales in the potential.     

A generalized preferential attachment model for business firms growth rates

We present a preferential attachment growth model to obtain the distribution P(K) of number of units K in the classes which may represent business firms or other socio-economic entities. We found that P(K) is described in its central part by a power law with an exponent ϕ = 2+b/(1-b) which depends on the probability of entry of new classes, b. In a particular problem of city population this distribution is equivalent to the well known Zipf law. In the absence of the new classes entry, the distribution P(K) is exponential. Using analytical form of P(K) and assuming proportional growth for units, we derive P(g), the distribution of business firm growth rates. The model predicts that P(g) has a Laplacian cusp in the central part and asymptotic power-law tails with an exponent ζ = 3. We test the analytical expressions derived using heuristic arguments by simulations. The model might also explain the size-variance relationship of the firm growth rates.