HemeBIND: a novel method for heme binding residue prediction by combining structural and sequence information

<p>Abstract</p> <p>Background</p> <p>Accurate prediction of binding residues involved in the interactions between proteins and small ligands is one of the major challenges in structural bioinformatics. Heme is an essential and commonly used ligand that plays critical roles in electron transfer, catalysis, signal transduction and gene expression. Although much effort has been devoted to the development of various generic algorithms for ligand binding site prediction over the last decade, no algorithm has been specifically designed to complement experimental techniques for identification of heme binding residues. Consequently, an urgent need is to develop a computational method for recognizing these important residues.</p> <p>Results</p> <p>Here we introduced an efficient algorithm HemeBIND for predicting heme binding residues by integrating structural and sequence information. We systematically investigated the characteristics of binding interfaces based on a non-redundant dataset of heme-protein complexes. It was found that several sequence and structural attributes such as evolutionary conservation, solvent accessibility, depth and protrusion clearly illustrate the differences between heme binding and non-binding residues. These features can then be separately used or combined to build the structure-based classifiers using support vector machine (SVM). The results showed that the information contained in these features is largely complementary and their combination achieved the best performance. To further improve the performance, an attempt has been made to develop a post-processing procedure to reduce the number of false positives. In addition, we built a sequence-based classifier based on SVM and sequence profile as an alternative when only sequence information can be used. Finally, we employed a voting method to combine the outputs of structure-based and sequence-based classifiers, which demonstrated remarkably better performance than the individual classifier alone.</p> <p>Conclusions</p> <p>HemeBIND is the first specialized algorithm used to predict binding residues in protein structures for heme ligands. Extensive experiments indicated that both the structure-based and sequence-based methods have effectively identified heme binding residues while the complementary relationship between them can result in a significant improvement in prediction performance. The value of our method is highlighted through the development of HemeBIND web server that is freely accessible at <url>http://mleg.cse.sc.edu/hemeBIND/</url>.</p

Innocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Is One Trial Sufficient to Obtain Excellent Pressure Pain Threshold Reliability in the Low Back of Asymptomatic Individuals? A Test-Retest Study.

The assessment of pressure pain threshold (PPT) provides a quantitative value related to the mechanical sensitivity to pain of deep structures. Although excellent reliability of PPT has been reported in numerous anatomical locations, its absolute and relative reliability in the lower back region remains to be determined. Because of the high prevalence of low back pain in the general population and because low back pain is one of the leading causes of disability in industrialized countries, assessing pressure pain thresholds over the low back is particularly of interest. The purpose of this study study was (1) to evaluate the intra- and inter- absolute and relative reliability of PPT within 14 locations covering the low back region of asymptomatic individuals and (2) to determine the number of trial required to ensure reliable PPT measurements. Fifteen asymptomatic subjects were included in this study. PPTs were assessed among 14 anatomical locations in the low back region over two sessions separated by one hour interval. For the two sessions, three PPT assessments were performed on each location. Reliability was assessed computing intraclass correlation coefficients (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for all possible combinations between trials and sessions. Bland-Altman plots were also generated to assess potential bias in the dataset. Relative reliability for both intra- and inter- session was almost perfect with ICC ranged from 0.85 to 0.99. With respect to the intra-session, no statistical difference was reported for ICCs and SEM regardless of the conducted comparisons between trials. Conversely, for inter-session, ICCs and SEM values were significantly larger when two consecutive PPT measurements were used for data analysis. No significant difference was observed for the comparison between two consecutive measurements and three measurements. Excellent relative and absolute reliabilities were reported for both intra- and inter-session. Reliable measurements can be equally achieved when using the mean of two or three consecutive PPT measurements, as usually proposed in the literature, or with only the first one. Although reliability was almost perfect regardless of the conducted comparison between PPT assessments, our results suggest using two consecutive measurements to obtain higher short term absolute reliability