Average Structures of a Single Knotted Ring Polymer

Two types of average structures of a single knotted ring polymer are studied by Brownian dynamics simulations. For a ring polymer with N segments, its structure is represented by a 3N -dimensional conformation vector consisting of the Cartesian coordinates of the segment positions relative to the center of mass of the ring polymer. The average structure is given by the average conformation vector, which is self-consistently defined as the average of the conformation vectors obtained from a simulation each of which is rotated to minimize its distance from the average conformation vector. From each conformation vector sampled in a simulation, 2N conformation vectors are generated by changing the numbering of the segments. Among the 2N conformation vectors, the one closest to the average conformation vector is used for one type of the average structure. The other type of the averages structure uses all the conformation vectors generated from those sampled in a simulation. In thecase of the former average structure, the knotted part of the average structure is delocalized for small N and becomes localized as N is increased. In the case of the latter average structure, the average structure changes from a double loop structure for small N to a single loop structure for large N, which indicates the localization-delocalization transition of the knotted part.Comment: 15 pages, 19 figures, uses jpsj2.cl

Introduction to protein folding for physicists

The prediction of the three-dimensional native structure of proteins from the knowledge of their amino acid sequence, known as the protein folding problem, is one of the most important yet unsolved issues of modern science. Since the conformational behaviour of flexible molecules is nothing more than a complex physical problem, increasingly more physicists are moving into the study of protein systems, bringing with them powerful mathematical and computational tools, as well as the sharp intuition and deep images inherent to the physics discipline. This work attempts to facilitate the first steps of such a transition. In order to achieve this goal, we provide an exhaustive account of the reasons underlying the protein folding problem enormous relevance and summarize the present-day status of the methods aimed to solving it. We also provide an introduction to the particular structure of these biological heteropolymers, and we physically define the problem stating the assumptions behind this (commonly implicit) definition. Finally, we review the 'special flavor' of statistical mechanics that is typically used to study the astronomically large phase spaces of macromolecules. Throughout the whole work, much material that is found scattered in the literature has been put together here to improve comprehension and to serve as a handy reference.Comment: 53 pages, 18 figures, the figures are at a low resolution due to arXiv restrictions, for high-res figures, go to http://www.pabloechenique.co

Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites

A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB

SGC - Structural Biology and Human Health: A New Approach to Publishing Structural Biology Results

The Structural Genomics Consortium (SGC) is a not-for-profit, public-private partnership established to deliver novel structural biology knowledge on proteins of medical relevance and place this information into the public domain without restriction, spearheading the concept of "Open-Source Science" to enable drug discovery. The SGC is a major provider of structural information focussed on proteins related to human health, contributing 20.5% of novel structures released by the PDB in 2008. In this article we describe the PLoS ONE Collection entitled 'Structural Biology and Human Health: Medically Relevant Proteins from the SGC'. This Collection contains a series of articles documenting many of the novel protein structures determined by the SGC and work to further characterise their function. Each article in this Collection can be read in an enhanced version where we have integrated our interactive and intuitive 3D visualisation platform, known as iSee. This publishing platform enables the communication of complex structural biology and related data to a wide audience of non-structural biologists. With the use of iSee as the first example of an interactive and intuitive 3D document publication method as part of PLoS ONE, we are pushing the boundaries of structural biology data delivery and peer-review. Our strong desire is that this step forward will encourage others to consider the need for publication of three dimensional and associated data in a similar manner. © 2009 Lee et al

Geoantineutrino Spectrum, 3He/4He-ratio Distribution in the Earth's Interior and Slow Nuclear Burning on the Boundary of the Liquid and Solid Phases of the Earth's Core

The description problem of geoantineutrino spectrum and reactor antineutrino experimental spectrum in KamLAND, which takes place for antineutrino energy \~2.8 MeV, and also the experimental results of the interaction of uranium dioxide and carbide with iron-nickel and silicaalumina melts at high pressure (5-10 GP?) and temperature (1600-2200C) have motivated us to consider the possible consequences of the assumption made by V.Anisichkin and coauthors that there is an actinid shell on boundary of liquid and solid phases of the Earth's core. We have shown that the activation of a natural nuclear reactor operating as the solitary waves of nuclear burning in 238U- and/or 232Th-medium (in particular, the neutron- fission progressive wave of Feoktistov and/or Teller-Ishikawa-Wood) can be such a physical consequence. The simplified model of the kinetics of accumulation and burnup in U-Pu fuel cycle of Feoktistov is developed. The results of the numerical simulation of neutron-fission wave in two-phase UO2/Fe medium on a surface of the Earth's solid core are presented. The georeactor model of 3He origin and the 3He/4He-ratio distribution in the Earth's interior is offered. It is shown that the 3He/4He ratio distribution can be the natural quantitative criterion of georeactor thermal power. On the basis of O'Nions-Evensen-Hamilton geochemical model of mantle differentiation and the crust growth supplied by actinid shell on the boundary of liquid and solid phases of the Earth's core as a nuclear energy source (georeactor with power of 30 TW), the tentative estimation of geoantineutrino intensity and geoantineutrino spectrum on the Earth surface are given.Comment: 28 pages, 12 figures. Added text, formulas, figures and references. Corrected equations. Changed content of some section

Substrate binding and translocation of the serotonin transporter studied by docking and molecular dynamics simulations

The serotonin (5-HT) transporter (SERT) plays an important role in the termination of 5-HT-mediated neurotransmission by transporting 5-HT away from the synaptic cleft and into the presynaptic neuron. In addition, SERT is the main target for antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs). The three-dimensional (3D) structure of SERT has not yet been determined, and little is known about the molecular mechanisms of substrate binding and transport, though such information is very important for the development of new antidepressant drugs. In this study, a homology model of SERT was constructed based on the 3D structure of a prokaryotic homologous leucine transporter (LeuT) (PDB id: 2A65). Eleven tryptamine derivates (including 5-HT) and the SSRI (S)-citalopram were docked into the putative substrate binding site, and two possible binding modes of the ligands were found. To study the conformational effect that ligand binding may have on SERT, two SERT–5-HT and two SERT–(S)-citalopram complexes, as well as the SERT apo structure, were embedded in POPC lipid bilayers and comparative molecular dynamics (MD) simulations were performed. Our results show that 5-HT in the SERT–5-HTB complex induced larger conformational changes in the cytoplasmic parts of the transmembrane helices of SERT than any of the other ligands. Based on these results, we suggest that the formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation

Computational modelling of NF-κB activation by IL-1RI and its co-receptor TILRR, predicts a role for Cytoskeletal Sequestration of IκBα in inflammatory signalling.

The transcription factor NF-κB (nuclear factor kappa B) is activated by Toll-like receptors and controlled by mechanotransduction and changes in the cytoskeleton. In this study we combine 3-D predictive protein modelling and in vitro experiments with in silico simulations to determine the role of the cytoskeleton in regulation of NF-κB. Simulations used a comprehensive agent-based model of the NF-κB pathway, which includes the type 1 IL-1 receptor (IL-1R1) complex and signalling intermediates, as well as cytoskeletal components. Agent based modelling relies on in silico reproductions of systems through the interactions of its components, and provides a reliable tool in investigations of biological processes, which require spatial considerations and involve complex formation and translocation of regulatory components. We show that our model faithfully reproduces the multiple steps comprising the NF-κB pathway, and provides a framework from which we can explore novel aspects of the system. The analysis, using 3-D predictive protein modelling and in vitro assays, demonstrated that the NF-κB inhibitor, IκBα is sequestered to the actin/spectrin complex within the cytoskeleton of the resting cell, and released during IL-1 stimulation, through a process controlled by the IL-1RI co-receptor TILRR (Toll-like and IL-1 receptor regulator). In silico simulations using the agent-based model predict that the cytoskeletal pool of IκBα is released to adjust signal amplification in relation to input levels. The results suggest that the process provides a mechanism for signal calibration and enables efficient, activation-sensitive regulation of NF-κB and inflammatory responses

Structural Basis for Substrate Specificity in Human Monomeric Carbonyl Reductases

Carbonyl reduction constitutes a phase I reaction for many xenobiotics and is carried out in mammals mainly by members of two protein families, namely aldo-keto reductases and short-chain dehydrogenases/reductases. In addition to their capacity to reduce xenobiotics, several of the enzymes act on endogenous compounds such as steroids or eicosanoids. One of the major carbonyl reducing enzymes found in humans is carbonyl reductase 1 (CBR1) with a very broad substrate spectrum. A paralog, carbonyl reductase 3 (CBR3) has about 70% sequence identity and has not been sufficiently characterized to date. Screening of a focused xenobiotic compound library revealed that CBR3 has narrower substrate specificity and acts on several orthoquinones, as well as isatin or the anticancer drug oracin. To further investigate structure-activity relationships between these enzymes we crystallized CBR3, performed substrate docking, site-directed mutagenesis and compared its kinetic features to CBR1. Despite high sequence similarities, the active sites differ in shape and surface properties. The data reveal that the differences in substrate specificity are largely due to a short segment of a substrate binding loop comprising critical residues Trp229/Pro230, Ala235/Asp236 as well as part of the active site formed by Met141/Gln142 in CBR1 and CBR3, respectively. The data suggest a minor role in xenobiotic metabolism for CBR3. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone-bromodomain interaction is of great importance. We have identified the 3,5 dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC50 values of <5 μM for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains