COPS—a novel workbench for explorations in fold space

The COPS (Classification Of Protein Structures) web server provides access to the complete repertoire of known protein structures and protein structural domains. The COPS classification encodes pairwise structural similarities as quantified metric relationships. The resulting metrical structure is mapped to a hierarchical tree, which is largely equivalent to the structure of a file browser. Exploiting this relationship we implemented the Fold Space Navigator, a tool that makes navigation in fold space as convenient as browsing through a file system. Moreover, pairwise structural similarities among the domains can be visualized and inspected instantaneously. COPS is updated weekly and stays concurrent with the PDB repository. The server also exposes the COPS classification pipeline. Newly determined structures uploaded to the server are chopped into domains, the locations of the new domains in the classification tree are determined, and their neighborhood can be immediately explored through the Fold Space Navigator. The COPS web server is accessible at http://cops.services.came.sbg.ac.at/

Potentials of Mean Force for Protein Structure Prediction Vindicated, Formalized and Generalized

Understanding protein structure is of crucial importance in science, medicine and biotechnology. For about two decades, knowledge based potentials based on pairwise distances -- so-called "potentials of mean force" (PMFs) -- have been center stage in the prediction and design of protein structure and the simulation of protein folding. However, the validity, scope and limitations of these potentials are still vigorously debated and disputed, and the optimal choice of the reference state -- a necessary component of these potentials -- is an unsolved problem. PMFs are loosely justified by analogy to the reversible work theorem in statistical physics, or by a statistical argument based on a likelihood function. Both justifications are insightful but leave many questions unanswered. Here, we show for the first time that PMFs can be seen as approximations to quantities that do have a rigorous probabilistic justification: they naturally arise when probability distributions over different features of proteins need to be combined. We call these quantities reference ratio distributions deriving from the application of the reference ratio method. This new view is not only of theoretical relevance, but leads to many insights that are of direct practical use: the reference state is uniquely defined and does not require external physical insights; the approach can be generalized beyond pairwise distances to arbitrary features of protein structure; and it becomes clear for which purposes the use of these quantities is justified. We illustrate these insights with two applications, involving the radius of gyration and hydrogen bonding. In the latter case, we also show how the reference ratio method can be iteratively applied to sculpt an energy funnel. Our results considerably increase the understanding and scope of energy functions derived from known biomolecular structures

Deriving amino acid contact potentials from their frequencies of occurence in proteins: a lattice model study

The possibility of deriving the contact potentials between amino acids from their frequencies of occurence in proteins is discussed in evolutionary terms. This approach allows the use of traditional thermodynamics to describe such frequencies and, consequently, to develop a strategy to include in the calculations correlations due to the spatial proximity of the amino acids and to their overall tendency of being conserved in proteins. Making use of a lattice model to describe protein chains and defining a "true" potential, we test these strategies by selecting a database of folding model sequences, deriving the contact potentials from such sequences and comparing them with the "true" potential. Taking into account correlations allows for a markedly better prediction of the interaction potentials

Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

Histone acetyltransferases (HATs) are interesting targets for the treatment of cancer and HIV infections but reports on selective inhibitors are very limited. Here we report structure–activity studies of pyrido- and benzisothiazolones in the in vitro inhibition of histone acetyltransferases, namely PCAF, CBP, Gcn5 and p300 using a heterogeneous assay with antibody mediated quantitation of the acetylation of a peptidic substrate. Dependent on the chemical structure distinct subtype selectivity profiles can be obtained. While N-aryl derivatives usually are rather pan-HAT inhibitors, N-alkyl derivatives show mostly a preference for CBP/p300. Selected compounds were also shown to be inhibitors of MOF. The best inhibitors show submicromolar inhibition of CBP. Selected compounds affect growth of HL-60 leukemic cells and LNCaP prostate carcinoma cells with higher potency on the leukemic cells. Target engagement was shown with reduction of histone acetylation in LNCaP cells

Lower objectively measured physical activity is linked with perceived risk of hypoglycemia in type 1 diabetes

Aims Compare physical activity (PA) levels in adults with and without type 1 diabetes and identify diabetes-specific barriers to PA. Methods Forty-four individuals with type 1 diabetes and 77 non-diabetic controls in the Coronary Artery Calcification in Type 1 Diabetes study wore an accelerometer for 2 weeks. Moderate-to-vigorous physical activity (MVPA) was compared by diabetes status using multiple linear regression. The Barriers to Physical Activity in Type 1 Diabetes questionnaire measured diabetes-specific barriers to PA, and the Clarke hypoglycemia awareness questionnaire measured hypoglycemia frequency. Results Individuals with type 1 diabetes engaged in less MVPA, fewer bouts of MVPA, and spent less time in MVPA bouts per week than individuals without diabetes (all p  0.05). The most common diabetes-specific barrier to PA was risk of hypoglycemia. Individuals with diabetes reporting barriers spent less time in MVPA bouts per week than those not reporting barriers (p = 0.047). Conclusions Individuals with type 1 diabetes engage in less MVPA than those without diabetes despite similar self-reported levels, with the main barrier being perceived risk of hypoglycemia. Adults with type 1 diabetes require guidance to meet current PA guidelines and reduce cardiovascular risk

The crust in the pamir: Insights from receiver functions

The Cenozoic convergence between India and Asia has created Earth's thickest crust in the Pamir‐Tibet Plateau by extreme crustal shortening. Here we study the crustal structure of the Pamir and western Tian Shan, the adjacent margins of the Tajik, Tarim, and Ferghana Basins, and the Hindu Kush, using data collected by temporary seismic experiments. We derive, compare, and combine independent observations from P and S receiver functions. The obtained Moho depth varies from ~40 km below the basins to a double‐normal thickness of 65–75 km underneath the Pamir and Hindu Kush. A Moho doublet—with the deeper interface down to a depth of ~90 km—coincides with the arc of intermediate‐depth seismicity underneath the Pamir, where Asian continental lower crust delaminates and rolls back. The crust beneath most of the Central and South Pamir has a low Vp/Vs ratio (<1.70), suggesting a dominantly felsic composition, probably a result of delamination/foundering of the mafic rocks of the lower crust. Beneath the Cenozoic gneiss domes of the Central and South Pamir, which represent extensional core complexes, the Vp/Vs ratios are moderate to high (~1.75), consistent with the previously observed, midcrustal low‐velocity zones, implying the presence of crustal partial melts. Even higher crustal average Vp/Vs ratios up to 1.90 are found in the sedimentary basins and along the Main Pamir Thrust. The ratios along the latter—the active thrust front of the Pamir—may reflect fluid accumulations within a strongly fractured fault system

Generalized-ensemble Monte carlo method for systems with rough energy landscape

We present a novel Monte Carlo algorithm which enhances equilibrization of low-temperature simulations and allows sampling of configurations over a large range of energies. The method is based on a non-Boltzmann probability weight factor and is another version of the so-called generalized-ensemble techniques. The effectiveness of the new approach is demonstrated for the system of a small peptide, an example of the frustrated system with a rugged energy landscape.Comment: Latex; ps-files include