A simplified exactly solvable model for beta-amyloid aggregation

We propose an exactly solvable simplified statistical mechanical model for the thermodynamics of beta-amyloid aggregation, generalizing a well-studied model for protein folding. The monomer concentration is explicitly taken into account as well as a non trivial dependence on the microscopic degrees of freedom of the single peptide chain, both in the alpha-helix folded isolated state and in the fibrillar one. The phase diagram of the model is studied and compared to the outcome of fibril formation experiments which is qualitatively reproduced.Comment: 4 pages, 2 figure

Exploring the correlation between the folding rates of proteins and the entanglement of their native states

The folding of a protein towards its native state is a rather complicated process. However there are empirical evidences that the folding time correlates with the contact order, a simple measure of the spatial organisation of the native state of the protein. Contact order is related to the average length of the main chain loops formed by amino acids which are in contact. Here we argue that folding kinetics can be influenced also by the entanglement that loops may undergo within the overall three dimensional protein structure. In order to explore such possibility, we introduce a novel descriptor, which we call "maximum intrachain contact entanglement". Specifically, we measure the maximum Gaussian entanglement between any looped portion of a protein and any other non-overlapping subchain of the same protein, which is easily computed by discretized line integrals on the coordinates of the $C_{\alpha}$ atoms. By analyzing experimental data sets of two-state and multistate folders, we show that also the new index is a good predictor of the folding rate. Moreover, being only partially correlated with previous methods, it can be integrated with them to yield more accurate predictions.Comment: 8 figures. v2: new titl

Linking in domain-swapped protein dimers

The presence of knots has been observed in a small fraction of single-domain proteins and related to their thermodynamic and kinetic properties. The exchanging of identical structural elements, typical of domain-swapped proteins, make such dimers suitable candidates to validate the possibility that mutual entanglement between chains may play a similar role for protein complexes. We suggest that such entanglement is captured by the linking number. This represents, for two closed curves, the number of times that each curve winds around the other. We show that closing the curves is not necessary, as a novel parameter $G'$, termed Gaussian entanglement, is strongly correlated with the linking number. Based on $110$ non redundant domain-swapped dimers, our analysis evidences a high fraction of chains with a significant intertwining, that is with $|G'| > 1$. We report that Nature promotes configurations with negative mutual entanglement and surprisingly, it seems to suppress intertwining in long protein dimers. Supported by numerical simulations of dimer dissociation, our results provide a novel topology-based classification of protein-swapped dimers together with some preliminary evidence of its impact on their physical and biological properties.Comment: v2: some new paragraphs and new abstrac

Melting behavior and different bound states in three-stranded DNA models

Thermal denaturation of DNA is often studied with coarse-grained models in which native sequential base pairing is mimicked by the existence of attractive interactions only between monomers at the same position along strands (Poland and Scheraga models). Within this framework, the existence of a three strand DNA bound state in conditions where a duplex DNA would be in the denaturated state was recently predicted from a study of three directed polymer models on simplified hierarchical lattices ($d>2$) and in $1+1$ dimensions. Such phenomenon which is similar to the Efimov effect in nuclear physics was named Efimov-DNA. In this paper we study the melting of the three-stranded DNA on a Sierpinski gasket of dimensions $d<2$ by assigning extra weight factors to fork openings and closings, to induce a two-strand DNA melting. In such a context we can find again the existence of the Efimov-DNA-like state but quite surprisingly we discover also the presence of a different phase, to be called a mixed state, where the strands are pair-wise bound but without three chain contacts. Whereas the Efimov DNA turns out to be a crossover near melting, the mixed phase is a thermodynamic phase.Comment: corrected file uploade

Unified perspective on proteins: A physics approach

We study a physical system which, while devoid of the complexity one usually associates with proteins, nevertheless displays a remarkable array of protein-like properties. The constructive hypothesis that this striking resemblance is not accidental leads not only to a unified framework for understanding protein folding, amyloid formation and protein interactions but also has implications for natural selection.Comment: 26 pages, 15 figures, to appear on Phys. Rev.

A simple and efficient statistical potential for scoring ensembles of protein structures

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Anti-Inflammatory activity of a polyphenolic extract from Arabidopsis thaliana in in vitro and in vivo models of Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of Arabidopsis thaliana (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ25⁻35 peptide and extract showed a lower pro-inflammatory (IL-6, IL-1β, TNF-α) and a higher anti-inflammatory (IL-4, IL-10, IL-13) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ1⁻42. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases

When a DNA Triple helix melts: An analog of the Efimov state

The base sequences of DNA contain the genetic code and to decode it a double helical DNA has to open its base pairs. Recent studies have shown that one can use a third strand to identify the base sequences without opening the double helix but by forming a triple helix. It is predicted here that such a three chain system exhibits the unusual behaviour of the existence of a three chain bound state in the absence of any two being bound. This phenomenon is analogous to the Efimov state in three particle quantum mechanics. A scaling theory is used to justify the Efimov connection. Real space renormalization group (RG), and exact numerical calculations are used to validate the prediction of a biological Efimov effect.Comment: Replaced by the (almost) published version, except the word "curiouser

Geometrical model for the native-state folds of proteins

We recently introduced a physical model [Hoang et al., P. Natl. Acad. Sci. USA (2004), Banavar et al., Phys. Rev. E (2004)] for proteins which incorporates, in an approximate manner, several key features such as the inherent anisotropy of a chain molecule, the geometrical and energetic constraints placed by the hydrogen bonds and sterics, and the role played by hydrophobicity. Within this framework, marginally compact conformations resembling the native state folds of proteins emerge as broad competing minima in the free energy landscape even for a homopolymer. Here we show how the introduction of sequence heterogeneity using a simple scheme of just two types of amino acids, hydrophobic (H) and polar (P), and sequence design allows a selected putative native fold to become the free energy minimum at low temperature. The folding transition exhibits thermodynamic cooperativity, if one neglects the degeneracy between two different low energy conformations sharing the same fold topology.Comment: 12 pages, 3 figure