Prediction of Protein Binding Regions in Disordered Proteins

Many disordered proteins function via binding to a structured partner and undergo a disorder-to-order transition. The coupled folding and binding can confer several functional advantages such as the precise control of binding specificity without increased affinity. Additionally, the inherent flexibility allows the binding site to adopt various conformations and to bind to multiple partners. These features explain the prevalence of such binding elements in signaling and regulatory processes. In this work, we report ANCHOR, a method for the prediction of disordered binding regions. ANCHOR relies on the pairwise energy estimation approach that is the basis of IUPred, a previous general disorder prediction method. In order to predict disordered binding regions, we seek to identify segments that are in disordered regions, cannot form enough favorable intrachain interactions to fold on their own, and are likely to gain stabilizing energy by interacting with a globular protein partner. The performance of ANCHOR was found to be largely independent from the amino acid composition and adopted secondary structure. Longer binding sites generally were predicted to be segmented, in agreement with available experimentally characterized examples. Scanning several hundred proteomes showed that the occurrence of disordered binding sites increased with the complexity of the organisms even compared to disordered regions in general. Furthermore, the length distribution of binding sites was different from disordered protein regions in general and was dominated by shorter segments. These results underline the importance of disordered proteins and protein segments in establishing new binding regions. Due to their specific biophysical properties, disordered binding sites generally carry a robust sequence signal, and this signal is efficiently captured by our method. Through its generality, ANCHOR opens new ways to study the essential functional sites of disordered proteins

Dynamics of open DNA sliding clamps

A range of enzymes in DNA replication and repair bind to DNA-clamps: torus-shaped proteins that encircle double-stranded DNA and act as mobile tethers. Clamps from viruses (such as gp45 from the T4 bacteriophage) and eukaryotes (PCNAs) are homotrimers, each protomer containing two repeats of the DNA-clamp motif, while bacterial clamps (pol III β) are homodimers, each protomer containing three DNA-clamp motifs. Clamps need to be flexible enough to allow opening and loading onto primed DNA by clamp loader complexes. Equilibrium and steered molecular dynamics simulations have been used to study DNA-clamp conformation in open and closed forms. The E. coli and PCNA clamps appear to prefer closed, planar conformations. Remarkably, gp45 appears to prefer an open right-handed spiral conformation in solution, in agreement with previously reported biophysical data. The structural preferences of DNA clamps in solution have implications for understanding the duty cycle of clamp-loaders

The contradiction between production and consumption as related to the study of crisis (4)

Abstract Objectives Further research into medical student attitudes towards older people is important, and requires accurate and detailed evaluative methodology. The two objectives for this paper are: (1) From the literature, to critically review instruments of measure for medical student attitudes towards older people, and (2) To recommend the most appropriate quantitative instrument for future research into medical student attitudes towards older people. Results A SCOPUS and Ovid cross search was performed using the keywords Attitude and medical student and aged or older or elderly. This search was supplemented by manual searching, guided by citations in articles identified by the initial literature search, using the SCOPUS and PubMed databases. International studies quantifying medical student attitudes have demonstrated neutral to positive attitudes towards older people, using various instruments. The most commonly used instruments are the Ageing Semantic Differential (ASD) and the University of California Los Angeles Geriatric Attitudes Scale, with several other measures occasionally used. All instruments used to date have inherent weaknesses. A reliable and valid instrument with which to quantify modern medical student attitudes towards older people has not yet been developed. Adaptation of the ASD for contemporary usage is recommended