Biomedical subjects

Paolo De Los Rios

Publications and source records attributed to Paolo De Los Rios.

10 recordsLinked to original sources

PubMed2006

Glasslike structure of globular proteins and the boson peak.

Vibrational spectra of proteins and topologically disordered solids display a common anomaly at low frequencies, known as boson peak. We show that such feature in globular proteins can be deciphered in terms of an energy landscape picture, as it is for glassy systems. Exploiting the tools of Euclidean random matrix theory, we clarify the physical origin of such anomaly in terms of a mechanical instability of the system. As a natural explanation, we argue that such instability is relevant for proteins in order for their molecular functions to be optimally rooted in their structures.

Animals↗

PubMed2006

Hsp70 chaperones accelerate protein translocation and the unfolding of stable protein aggregates by entropic pulling.

Hsp70s are highly conserved ATPase molecular chaperones mediating the correct folding of de novo synthesized proteins, the translocation of proteins across membranes, the disassembly of some native protein oligomers, and the active unfolding and disassembly of stress-induced protein aggregates. Here, we bring thermodynamic arguments and biochemical evidences for a unifying mechanism named entropic pulling, based on entropy loss due to excluded-volume effects, by which Hsp70 molecules can convert the energy of ATP hydrolysis into a force capable of accelerating the local unfolding of various protein substrates and, thus, perform disparate cellular functions. By means of entropic pulling, individual Hsp70 molecules can accelerate unfolding and pulling of translocating polypeptides into mitochondria in the absence of a molecular fulcrum, thus settling former contradictions between the power-stroke and the Brownian ratchet models for Hsp70-mediated protein translocation across membranes. Moreover, in a very different context devoid of membrane and components of the import pore, the same physical principles apply to the forceful unfolding, solubilization, and assisted native refolding of stable protein aggregates by individual Hsp70 molecules, thus providing a mechanism for Hsp70-mediated protein disaggregation.

Bacterial Proteins↗

PubMed2006

Physical realizability of small-world networks.

Supplementing a lattice with long-range connections effectively models small-world networks characterized by a high local and global interconnectedness observed in systems ranging from society to the brain. If the links have a wiring cost associated with their length l, the corresponding distribution q(l) plays a crucial role. Uniform length distributions have received the most attention despite indications that q(l) approximately l(-alpha) exists-e.g., for integrated circuits, the Internet, and cortical networks. While length distributions of this type were previously examined in the context of navigability, we here discuss for such systems the emergence and physical realizability of small-world topology. Our simple argument allows us to understand under which condition and at what expense a small world results.

Journal Article↗

PubMed2005

Finding instabilities in the community structure of complex networks.

The problem of finding clusters in complex networks has been studied by mathematicians, computer scientists, and, more recently, by physicists. Many of the existing algorithms partition a network into clear clusters without overlap. Here we introduce a method to identify the nodes lying "between clusters," allowing for a general measure of the stability of the clusters. This is done by adding noise over the edge weights. Our method can in principle be used with almost any clustering algorithm able to deal with weighted networks. We present several applications on real-world networks using two different clustering algorithms.

Journal Article↗

PubMed2005

Effective interactions between chaotropic agents and proteins.

Chaotropic agents are cosolutes that can disrupt the hydrogen bonding network between water molecules and reduce the stability of the native state of proteins by weakening the hydrophobic effect. In this work, we represent the chaotropic agent as a factor that reduces the amount of order in the structures formed by water molecules, both in the bulk and the hydration shells around hydrophobic amino acids. In this framework we show that low chaotrope concentrations lead to a destabilization of the native state of proteins, and that high concentrations induce complete denaturation. We also find that the reduction of the number of bulk ordered states of water molecules can give origin to an effective interaction between chaotropic molecules and proteins.

Entropy↗

PubMed2005

Scaling exponents and probability distributions of DNA end-to-end distance.

The scaling of the average gyration radius of polymers as a function of their length can be experimentally determined from ensemble measurements, such as light scattering, and agrees with analytical estimates. Ensemble techniques, yet, do not give access to the full probability distributions. Single molecule techniques, instead, can deliver information on both average quantities and distribution functions. Here we exploit the high resolution of atomic force microscopy over long DNA molecules adsorbed on a surface to measure the average end-to-end distance as a function of the DNA length, and its full distribution function. We find that all the scaling exponents are close to the predicted 3D values (upsilon=0.589+/-0.006 and delta=2.58+/-0.77). These results suggest that the adsorption process is akin to a geometric projection from 3D to 2D, known to preserve the scaling properties of fractal objects of dimension df<2.

Computer Simulation↗

PubMed2005

Functional dynamics of PDZ binding domains: a normal-mode analysis.

Postsynaptic density-95/disks large/zonula occludens-1 (PDZ) domains are relatively small (80-120 residues) protein binding modules central in the organization of receptor clusters and in the association of cellular proteins. Their main function is to bind C-terminals of selected proteins that are recognized through specific amino acids in their carboxyl end. Binding is associated with a deformation of the PDZ native structure and is responsible for dynamical changes in regions not in direct contact with the target. We investigate how this deformation is related to the harmonic dynamics of the PDZ structure and show that one low-frequency collective normal mode, characterized by the concerted movements of different secondary structures, is involved in the binding process. Our results suggest that even minimal structural changes are responsible for communication between distant regions of the protein, in agreement with recent NMR experiments. Thus, PDZ domains are a very clear example of how collective normal modes are able to characterize the relation between function and dynamics of proteins, and to provide indications on the precursors of binding/unbinding events.

Adenosine Triphosphate↗

PubMed2004

Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability.

Kosmotropic cosolvents added to an aqueous solution promote the aggregation of hydrophobic solute particles, while chaotropic cosolvents act to destabilise such aggregates. We discuss the mechanism for these phenomena within an adapted version of the two-state Muller-Lee-Graziano model for water, which provides a complete description of the ternary water/cosolvent/solute system for small solute particles. This model contains the dominant effect of a kosmotropic substance, which is to enhance the formation of water structure. The consequent preferential exclusion both of cosolvent molecules from the solvation shell of hydrophobic particles and of these particles from the solution leads to a stabilisation of aggregates. By contrast, chaotropic substances disrupt the formation of water structure, are themselves preferentially excluded from the solution, and thereby contribute to solvation of hydrophobic particles. We use Monte Carlo simulations to demonstrate at the molecular level the preferential exclusion or binding of cosolvent molecules in the solvation shell of hydrophobic particles, and the consequent enhancement or suppression of aggregate formation. We illustrate the influence of structure-changing cosolvents on effective hydrophobic interactions by modelling qualitatively the kosmotropic effect of sodium chloride and the chaotropic effect of urea.

Binding Sites↗

PubMed2004

Cluster approximations for epidemic processes: a systematic description of correlations beyond the pair level.

The spread of a virus is an example of a dynamic process occurring on a discrete spatial arrangement. While the mean-field approximation reasonably reproduces the spreading behaviour for topologies where the number of connections per node is either high or strongly fluctuating and for those that show small-world features, it is inaccurate for lattice structured populations. Various improvements upon the ordinary pair approximation based on a number of assumptions concerning the higher-order correlations have been proposed. To find approaches that allow for a derivation of their dynamics remains a great challenge. By representing the population with its connectivity patterns as a homogeneous network, we propose a systematic methodology for the description of the epidemic dynamics that takes into account spatial correlations up to a desired range. The equations that the dynamical correlations are subject to are derived in a straightforward way, and they are solved very efficiently due to their binary character. The method embeds very naturally spatial patterns such as the presence of loops characterizing the square lattice or the tree-like structure ubiquitous in random networks, providing an improved description of the steady state as well as the invasion dynamics.

Cluster Analysis↗

PubMed2004

Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual hsp70 chaperones.

Hsp70 is a central molecular chaperone that passively prevents protein aggregation and uses the energy of ATP hydrolysis to solubilize, translocate, and mediate the proper refolding of proteins in the cell. Yet, the molecular mechanism by which the active Hsp70 chaperone functions are achieved remains unclear. Here, we show that the bacterial Hsp70 (DnaK) can actively unfold misfolded structures in aggregated polypeptides, leading to gradual disaggregation. We found that the specific unfolding and disaggregation activities of individual DnaK molecules were optimal for large aggregates but dramatically decreased for small aggregates. The active unfolding of the smallest aggregates, leading to proper global refolding, required the cooperative action of several DnaK molecules per misfolded polypeptide. This finding suggests that the unique ATP-fueled locking/unlocking mechanism of the Hsp70 chaperones can recruit random chaperone motions to locally unfold misfolded structures and gradually disentangle stable aggregates into refoldable proteins.

Chromatography, Gel↗