Influence of correlations on molecular recognition

The influence of the patchiness and correlations in the distribution of hydrophobic and polar residues at the interface between two rigid biomolecules on their recognition ability is investigated in idealised coarse-grained lattice models. A general two-stage approach is utilised where an ensemble of probe molecules is designed first and the recognition ability of the probe ensemble is related to the free energy of association with both the target molecule and a different rival molecule in a second step. The influence of correlation effects are investigated using numerical Monte Carlo techniques and mean field methods. Correlations lead to different optimum characteristic lengths of the hydrophobic and polar patches for the mutual design of the two biomolecules on the one hand and their recognition ability in the presence of other molecules on the other hand.Comment: 15 pages, 5 figure

Optimising the management of vaginal discharge syndrome in Bulgaria: cost effectiveness of four clinical algorithms with risk assessment

OBJECTIVES: To evaluate the performance and cost effectiveness of the WHO recommendations of incorporating risk-assessment scores and population prevalence of Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) into vaginal discharge syndrome (VDS) algorithms. METHODS: Non-pregnant women presenting with VDS were recruited at a non-governmental sexual health clinic in Sofia, Bulgaria. NG and CT were diagnosed by PCR and vaginal infections by microscopy. Risk factors for NG/CT were identified in multivariable analysis. Four algorithms based on different combinations of behavioural factors, clinical findings and vaginal microscopy were developed. Performance of each algorithm was evaluated for detecting vaginal and cervical infections separately. Cost effectiveness was based on cost per patient treated and cost per case correctly treated. Sensitivity analysis explored the influence of NG/CT prevalence on cost effectiveness. RESULTS: 60% (252/420) of women had genital infections, with 9.5% (40/423) having NG/CT. Factors associated with NG/CT included new and multiple sexual partners in the past 3 months, symptomatic partner, childlessness and >or=10 polymorphonuclear cells per field on vaginal microscopy. For NG/CT detection, the algorithm that relied solely on behavioural risk factors was less sensitive but more specific than those that included speculum examination or microscopy but had higher correct-treatment rate and lower over-treatment rates. The cost per true case treated using a combination of risk factors, speculum examination and microscopy was euro 24.08. A halving and tripling of NG/CT prevalence would have approximately the inverse impact on the cost-effectiveness estimates. CONCLUSIONS: Management of NG/CT in Bulgaria was improved by the use of a syndromic approach that included risk scores. Approaches that did not rely on microscopy lost sensitivity but were more cost effective

Does One Size Fit All? Drug Resistance and Standard Treatments: Results of Six Tuberculosis Programmes in Former Soviet Countries.

SETTING: After the collapse of the Soviet Union, countries in the region faced a dramatic increase in tuberculosis cases and the emergence of drug resistance. OBJECTIVE: To discuss the relevance of the DOTS strategy in settings with a high prevalence of drug resistance. DESIGN: Retrospective analysis of one-year treatment outcomes of short-course chemotherapy (SCC) and results of drug susceptibility testing (DST) surveys of six programmes located in the former Soviet Union: Kemerovo prison, Russia; Abkhasia, Georgia; Nagorno-Karabagh, Azerbaijan; Karakalpakstan, Uzbekistan; Dashoguz Velayat, Turkmenistan; and South Kazakhstan Oblast, Kazakhstan. Results are reported for new and previously treated smear-positive patients. RESULTS: Treatment outcomes of 3090 patients and DST results of 1383 patients were collected. Treatment success rates ranged between 87% and 61%, in Nagorno-Karabagh and Kemerovo, respectively, and failure rates between 7% and 23%. Any drug resistance ranged between 66% and 31% in the same programmes. MDR rates ranged between 28% in Karakalpakstan and Kemerovo prison and 4% in Nagorno-Karabagh. CONCLUSION: These results show the limits of SCC in settings with a high prevalence of drug resistance. They demonstrate that adapting treatment according to resistance patterns, access to reliable culture, DST and good quality second-line drugs are necessary

Residual Stress State of X65 Pipeline Girth Welds before and after Local and Furnace Post Weld Heat Treatment

This research investigated the effects of global (in other words, furnace-based) and local post weld heat treatment (PWHT) on residual stress (RS) relaxation in API 5L X65 pipe girth welds. All pipe spools were fabricated using identical pipeline production procedures for manufacturing multipass narrow gap welds. Nondestructive neutron diffraction (ND) strain scanning was carried out on girth welded pipe spools and strain-free comb samples for the determination of the lattice spacing. All residual stress measurements were carried out at the KOWARI strain scanning instrument at the Australian Nuclear Science and Technology Organization (ANSTO). Residual stresses were measured on two pipe spools in as-welded condition and two pipe spools after local and furnace PWHT. Measurements were conducted through the thickness in the weld material and adjacent parent metal starting from the weld toes. Besides, three line-scans along pipe length were made 3 mm below outer surface, at pipe wall midthickness, and 3 mm above the inner surface. PWHT was carried out for stress relief; one pipe was conventionally heat treated entirely in an enclosed furnace, and the other was locally heated by a flexible ceramic heating pad. Residual stresses measured after PWHT were at exactly the same locations as those in as-welded condition. Residual stress states of the pipe spools in as-welded condition and after PWHT were compared, and the results were presented in full stress maps. Additionally, through-thickness residual stress profiles and the results of one line scan (3 mm below outer surface) were compared with the respective residual stress profiles advised in British Standard BS 7910 “Guide to methods for assessing the acceptability of flaws in metallic structures” and the UK nuclear industry's R6 procedure. The residual stress profiles in as-welded condition were similar. With the given parameters, local PWHT has effectively reduced residual stresses in the pipe spool to such a level that it prompted the thought that local PWHT can be considered a substitute for global PWHT.</jats:p

Role of the Subunits Interactions in the Conformational Transitions in Adult Human Hemoglobin: an Explicit Solvent Molecular Dynamics Study

Hemoglobin exhibits allosteric structural changes upon ligand binding due to the dynamic interactions between the ligand binding sites, the amino acids residues and some other solutes present under physiological conditions. In the present study, the dynamical and quaternary structural changes occurring in two unligated (deoxy-) T structures, and two fully ligated (oxy-) R, R2 structures of adult human hemoglobin were investigated with molecular dynamics. It is shown that, in the sub-microsecond time scale, there is no marked difference in the global dynamics of the amino acids residues in both the oxy- and the deoxy- forms of the individual structures. In addition, the R, R2 are relatively stable and do not present quaternary conformational changes within the time scale of our simulations while the T structure is dynamically more flexible and exhibited the T\rightarrow R quaternary conformational transition, which is propagated by the relative rotation of the residues at the {\alpha}1{\beta}2 and {\alpha}2{\beta}1 interface.Comment: Reprinted (adapted) with permission from J. Phys. Chem. B DOI:10.1021/jp3022908. Copyright (2012) American Chemical Societ

Theory and simulation of short-range models of globular protein solutions

We report theoretical and simulation studies of phase coexistence in model globular protein solutions, based on short-range, central, pair potential representations of the interaction among macro-particles. After reviewing our previous investigations of hard-core Yukawa and generalised Lennard-Jones potentials, we report more recent results obtained within a DLVO-like description of lysozyme solutions in water and added salt. We show that a one-parameter fit of this model based on Static Light Scattering and Self-Interaction Chromatography data in the dilute protein regime, yields demixing and crystallization curves in good agreement with experimental protein-rich/protein-poor and solubility envelopes. The dependence of cloud and solubility points temperature of the model on the ionic strength is also investigated. Our findings highlight the minimal assumptions on the properties of the microscopic interaction sufficient for a satisfactory reproduction of the phase diagram topology of globular protein solutions.Comment: 17 pages, 8 figures, Proc. of Conference "Structural Arrest Transitions in Colloidal Systems with Short-Range Attractions", Messina (ITALY) 17-20 December 200

Palaeontological data about the climatic trends from Chattian to present along the Northeastern Atlantic frontage

Climatic changes that affected the Northeastern Atlantic frontage are analyzed on the basis of the evolution of faunas and floras from the late Oligocene onwards. The study deals with calcareous nannoplankton, marine micro- and macrofaunas, some terrestrial vertebrates and vegetal assemblages. The climate, first tropical, underwent a progressive cooling (North-South thermic gradient). Notable climatic deteriorations (withdrawal towards the South or disappearance of taxa indicative of warm climate and appearance of "cold" taxa) are evidenced mainly during the Middle Miocene and the late Pliocene. Faunas and floras of modern pattern have regained, after the Pleistocene glaciations, a new climatic ranging of a temperate type in the northern part

Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

SnugDock: Paratope Structural Optimization during Antibody-Antigen Docking Compensates for Errors in Antibody Homology Models

High resolution structures of antibody-antigen complexes are useful for analyzing the binding interface and to make rational choices for antibody engineering. When a crystallographic structure of a complex is unavailable, the structure must be predicted using computational tools. In this work, we illustrate a novel approach, named SnugDock, to predict high-resolution antibody-antigen complex structures by simultaneously structurally optimizing the antibody-antigen rigid-body positions, the relative orientation of the antibody light and heavy chains, and the conformations of the six complementarity determining region loops. This approach is especially useful when the crystal structure of the antibody is not available, requiring allowances for inaccuracies in an antibody homology model which would otherwise frustrate rigid-backbone docking predictions. Local docking using SnugDock with the lowest-energy RosettaAntibody homology model produced more accurate predictions than standard rigid-body docking. SnugDock can be combined with ensemble docking to mimic conformer selection and induced fit resulting in increased sampling of diverse antibody conformations. The combined algorithm produced four medium (Critical Assessment of PRediction of Interactions-CAPRI rating) and seven acceptable lowest-interface-energy predictions in a test set of fifteen complexes. Structural analysis shows that diverse paratope conformations are sampled, but docked paratope backbones are not necessarily closer to the crystal structure conformations than the starting homology models. The accuracy of SnugDock predictions suggests a new genre of general docking algorithms with flexible binding interfaces targeted towards making homology models useful for further high-resolution predictions

A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins