1,721,109 research outputs found
Expression and Role of Heparan Sulfated Proteoglycans in Pancreatic Cancer
Full text linkPancreatic cancer is a lethal condition with poor outcomes and an increasing incidence. The unfavourable prognosis is due to the lack of early symptoms and consequent late diagnosis. An effective method for the early diagnosis of pancreatic cancer is therefore sought by many researchers in the field. Heparan sulfated proteoglycan-related genes are often expressed differently in tumors than in normal tissues. Alteration of the tumor microenvironment is correlated with the ability of heparan sulfated proteoglycans to bind cytokines and growth factors and eventually to influence tumor progression. Here we discuss the importance of glypicans, syndecans, perlecan and extracellular matrix modifying enzymes, such as heparanases and sulfatases, as potential diagnostics in pancreatic cancer. We also ran an analysis on a multidimensional cancer genomics database for heparan sulfated proteoglycan-related genes, and report altered expression of some of them
On Conduction and Gating in K+-Channels
No full textPotassium channels can conduct passively K+ ions with rates of up to ∼ 108 ions per second at physiological conditions, and they are selective to these species by a factor of 104 over Na+ ions. Ion conduction has been proposed to involve transitions between two main states, with two or three K+ ions occupying the selectivity filter separated by an intervening water molecule. The largest free energy barrier of such a process was reported to be of the order of 2-3kcal mol−1. Here, we present an alternative mechanism for conduction of K+ in K+ channels where site vacancies are involved, and we propose that coexistence of several ion permeation mechanisms is energetically possible. Conduction can be described as a more anarchic phenomenon than previously characterized by the concerted translocations of K+-water-K+. Experiments also suggest that local structural changes in the selectivity filter may act as the a gate referred to as C-type inactivation. An extensive computational study on KirBac, is presented which supports the existence of a physical gate or constriction in the selectivity filter of K+ channels. Our computations identify a new selectivity filter structure, which is likely associated with C-type inactivation
K(+) and Na(+) conduction in selective and nonselective ion channels via molecular dynamics simulations.
No full textGenerations of scientists have been captivated by ion channels and how they control the workings of the cell by admitting ions from one side of the cell membrane to the other. Elucidating the molecular determinants of ion conduction and selectivity are two of the most fundamental issues in the field of biophysics. Combined with ongoing progress in structural studies, modeling and simulation have been an integral part of the development of the field. As of this writing, the relentless growth in computational power, the development of new algorithms to tackle the so-called rare events, improved force-field parameters, and the concomitant increasing availability of membrane protein structures, allow simulations to contribute even further, providing more-complete models of ion conduction and selectivity in ion channels. In this report, we give an overview of the recent progress made by simulation studies on the understanding of ion permeation in selective and nonselective ion channels
Computational studies of transport in ion channels using metadynamics
Full text linkMolecular dynamics simulations have played a fundamental role in numerous fields of science by providing insights into the structure and dynamics of complex systems at the atomistic level. However, exhaustive sampling by standard molecular dynamics is in most cases computationally prohibitive, and the time scales accessible remain significantly shorter than many biological processes of interest. In particular, in the study of ion channels, realistic models to describe permeation and gating require accounting for large numbers of particles and accurate interaction potentials, which severely limits the length of the simulations. To overcome such limitations, several advanced methods have been proposed among which is metadynamics. In this algorithm, an external bias potential to accelerate sampling along selected collective variables is introduced. This bias potential discourages visiting regions of the configurational space already explored. In addition, the bias potential provides an estimate of the free energy as a function of the collective variables chosen once the simulation has converged. In this review, recent contributions of metadynamics to the field of ion channels are discussed, including how metadynamics has been used to search for transition states, predict permeation pathways, treat conformational flexibility that underlies the coupling between gating and permeation, or compute free energy of permeation profiles. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov
Atypical mechanism of conduction in potassium channels.
No full textPotassium channels can conduct passively K+ ions with rates of up to approximately 10(8) ions per second at physiological conditions, and they are selective to these species by a factor of 10(4) over Na+ ions. Ion conduction has been proposed to involve transitions between 2 main states, with 2 or 3 K+ ions occupying the selectivity filter separated by an intervening water molecule. The largest free energy barrier of such a process was reported to be of the order of 2-3 kcal mol(-1). Here, we present an alternative mechanism for conduction of K+ in potassium channels where site vacancies are involved, and we propose that coexistence of several ion permeation mechanisms is energetically possible. Conduction can be described as a more anarchic phenomenon than previously characterized by the concerted translocations of K+-water-K+
Ion-triggered selectivity in bacterial sodium channels
Full text linkSince the availability of the first crystal structure of a bacterial Na+ channel in 2011, understanding selectivity across this family of membrane proteins has been the subject of intense research efforts. Initially, free energy calculations based on molecular dynamics simulations revealed that although sodium ions can easily permeate the channel with their first hydration shell almost intact, the selectivity filter is too narrow for efficient conduction of hydrated potassium ions. This steric view of selectivity was subsequently questioned by microsecond atomic trajectories, which proved that the selectivity filter appears to the permeating ions as a highly degenerate, liquid-like environment. Although this liquid-like environment looks optimal for rapid conduction of Na+, it seems incompatible with efficient discrimination between similar ion species, such as Na+ and K+, through steric effects. Here extensive molecular dynamics simulations, combined with Markov state model analyses, reveal that at positive membrane potentials, potassium ions trigger a conformational change of the selectivity toward a nonconductive metastable state. It is this transition of the selectivity filter, and not steric effects, that prevents the outward flux of K+ at positive membrane potentials. This description of selectivity, triggered by the nature of the permeating ions, might have implications on the current understanding of how ion channels, and in particular bacterial Na+ channels, operate at the atomic scale.</p
Molecular dynamics simulations of the TrkH membrane protein.
No full textTrkH is a transmembrane protein that mediates uptake of K(+) through the cell membrane. Despite the recent determination of its crystallographic structure, the nature of the permeation mechanism is still unknown, that is, whether K(+) ions move across TrkH by active transport or passive diffusion. Here, molecular dynamics simulations and the umbrella sampling technique have been employed to shed light on this question. The existence of binding site S3 and two alternative binding sites have been characterized. Analysis of the coordination number renders values that are almost constant, with a full contribution from the carbonyls of the protein only at S3. This observation contrasts with observations of K(+) channels, where the contribution of the protein to the coordination number is roughly constant in all four binding sites. An intramembrane loop is found immediately after the selectivity filter at the intracellular side of the protein, which obstructs the permeation pathway, and this is reflected in the magnitude of the energy barriers
Blocking the passage: C<inf>60</inf> geometrically clogs K<sup>+</sup> channels
Full text linkClassical molecular dynamics (MD) simulations combined with docking calculations, potential of mean force estimates with the umbrella sampling method, and molecular mechanic/Poisson-Boltzmann surface area (MM-PBSA) energy calculations reveal that C60 may block K(+) channels with two mechanisms: a low affinity blockage from the extracellular side, and an open-channel block from the intracellular side. The presence of a low affinity binding-site at the extracellular entrance of the channel is in agreement with the experimental results showing a fast and reversible block without use-dependence, from the extracellular compartment. Our simulation protocol suggests the existence of another binding site for C60 located in the channel cavity at the intracellular entrance of the selectivity filter. The escape barrier from this binding site is ∼21 kcal/mol making the corresponding kinetic rate of the order of minutes. The analysis of the change in solvent accessible surface area upon C60 binding shows that binding at this site is governed purely by shape complementarity, and that the molecular determinants of binding are conserved in the entire family of K(+) channels. The presence of this high-affinity binding site conserved among different K(+) channels may have serious implications for the toxicity of carbon nanomaterials
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