A binding event converted into a folding event

AbstractWe have designed a chimeric protein by connecting a circular permutant of the α-spectrin SH3 domain to the proline-rich decapeptide APSYSPPPPP with a three-residue link. Our aim was to obtain a single-chain protein with a tertiary fold that would mimic the binding between SH3 domains and proline-rich peptides. A comparison of the circular-dichroism and fluorescence spectra of the purified chimera and the SH3 circular permutant showed that the proline-rich sequence occupies the putative SH3 binding site in a similar conformation and with comparable interactions to those found in complexes between SH3 and proline-rich peptides. Differential scanning calorimetry indicated that the interactions in the binding motif interface are highly cooperative with the rest of the structure and thus the protein unfolds in a two-state process. The chimera is more stable than the circular permutant SH3 by 6–8 kJ mol−1 at 25°C and the difference in their unfolding enthalpy is approximately 32 kJ mol−1, which coincides with the values found for the binding of proline-rich peptides to SH3 domains. This type of chimeric protein may be useful in designing SH3 peptide ligands with improved affinity and specificity

SELEX RICH Performance and Physics Results

SELEX took data in the 1996/7 Fixed Target Run at Fermilab. The excellent performance parameters of the SELEX RICH Detector had direct influence on the quality of the obtained physics results.Comment: Contributed talk at the Fourth Workshop on RICH Detectors, June 5-10, 2002, Pylos, Greece. Accepted for publication in NIM

Компьютерное прогнозирование спектров биологической активности химических соединений: возможности и ограничения

oai:www.bmc-rm.org:article/4An essential characteristic of chemical compounds is their biological activity since its presence can become the basis for the use of the substance for therapeutic purposes, or, on the contrary, limit the possibilities of its practical application due to the manifestation of side action and toxic effects. Computer assessment of the biological activity spectra makes it possible to determine the most promising directions for the study of the pharmacological action of particular substances, and to filter out potentially dangerous molecules at the early stages of research. For more than 25 years, we have been developing and improving the computer program PASS (Prediction of Activity Spectra for Substances), designed to predict the biological activity spectrum of substance based on the structural formula of its molecules. The prediction is carried out by the analysis of structure-activity relationships for the training set, which currently contains information on structures and known biological activities for more than one million molecules. The structure of the organic compound is represented in PASS using Multilevel Neighborhoods of Atoms descriptors; the activity prediction for new compounds is performed by the naive Bayes classifier and the structure-activity relationships determined by the analysis of the training set. We have created and improved both local versions of the PASS program and freely available web resources based on PASS (http://www.way2drug.com). They predict several thousand biological activities (pharmacological effects, molecular mechanisms of action, specific toxicity and adverse effects, interaction with the unwanted targets, metabolism and action on molecular transport), cytotoxicity for tumor and non-tumor cell lines, carcinogenicity, induced changes of gene expression profiles, metabolic sites of the major enzymes of the first and second phases of xenobiotics biotransformation, and belonging to substrates and/or metabolites of metabolic enzymes. The web resource Way2Drug is used by over 19 000 researchers from more than 100 countries around the world, which allowed them to obtain over 600 000 predictions and publish about 500 papers describing the obtained results. The analysis of the published works shows that in some cases the interpretation of the prediction results presented by the authors of these publications requires an adjustment. In this work, we provide the theoretical basis and consider, on particular examples, the opportunities and limitations of computer-aided prediction of biological activity spectra.Важной характеристикой химических соединений является их биологическая активность, поскольку ее наличие может стать основой для использования вещества в терапевтических целях, либо, напротив, ограничить возможности его практического применения вследствие проявления побочных и токсических эффектов. Компьютерная оценка спектра биологической активности дает возможность определить наиболее перспективные направления для тестирования фармакологического действия конкретных веществ и отсеять потенциально опасные молекулы на ранних стадиях исследований. Свыше 25 лет нами осуществляется разработка и совершенствование компьютерной программы PASS (Prediction of Activity Spectra for Substances), предназначенной для прогнозирования спектра биологической активности вещества по структурной формуле его молекул. Прогноз осуществляется на основе анализа зависимостей «структура-активность» для соединений обучающей выборки, в настоящее время содержащей информацию о структурах и известных видах биологической активности более чем для миллиона молекул. Описание структуры молекул органического соединения реализовано в PASS посредством дескрипторов атомных окрестностей (Multilevel Neighborhoods of Atoms), прогнозирование активности для новых соединений выполняется алгоритмом на основе «наивного Байесовского подхода» и зависимостей «структура-активность», выявляемых при анализе обучающей выборки. Нами созданы и совершенствуются как локальные версии программы PASS, так и свободно доступные в Интернет веб-ресурсы на основе PASS (http://way2drug.com): прогноз нескольких тысяч видов биологической активности (фармакологические эффекты, молекулярные механизмы действия, специфическая токсичность и побочное действие, метаболизм, а также влияние на нежелательные мишени, молекулярный транспорт, генную экспрессию), прогноз цитотоксичности для опухолевых и неопухолевых клеточных линий, прогноз канцерогенности, прогноз индуцированных органическими соединениями изменений профилей экспрессии генов, прогноз взаимодействия с ферментами метаболизма лекарств, в том числе прогноз сайтов метаболизма, а также прогноз принадлежности к субстратам и/или метаболитам этих ферментов. Веб-ресурс Way2Drug используют свыше 19 тысяч исследователей более чем из 100 стран мира, что позволило им осуществить свыше 600 тысяч прогнозов и опубликовать около 500 работ с описанием полученных результатов. Анализ опубликованных работ показывает, что в некоторых случаях приводимая авторами этих публикаций интерпретация результатов прогноза требует корректировки. В рамках настоящей работы мы представим теоретическое обоснование и рассмотрим на конкретных примерах возможности и ограничения компьютерного прогнозирования спектров биологической активности

Measurement of the Ds lifetime

We report precise measurement of the Ds meson lifetime. The data were taken by the SELEX experiment (E781) spectrometer using 600 GeV/c Sigma-, pi- and p beams. The measurement has been done using 918 reconstructed Ds. The lifetime of the Ds is measured to be 472.5 +- 17.2 +- 6.6 fs, using K*(892)0K+- and phi pi+- decay modes. The lifetime ratio of Ds to D0 is 1.145+-0.049.Comment: 5 pages, 2 figures submitted to Phys. Lett.

Confirmation of the Double Charm Baryon Xi_cc+ via its Decay to p D+ K-

We observes a signal for the double charm baryon Xi_cc+ in the charged decay mode Xi_cc+ -> p D+ K- to complement the previously reported decay Xi_cc+ -> Lambda_c K- pi+ in data from SELEX, the charm hadro-production experiment (E781) at Fermilab. In this new decay mode we observe an excess of 5.62 events over an expected background estimated by event mixing to be 1.38+/-0.13 events. The Poisson probability that a background fluctuation can produce the apparent signal is less than 6.4E-4. The observed mass of this state is (3518+/-3)MeV/c^2, consistent with the published result. Averaging the two results gives a mass of (3518.7+/-1.7)MeV/c^2. The observation of this new weak decay mode confirms the previous SELEX suggestion that this state is a double charm baryon. The relative branching ratio Gamma(Xi_cc+ -> pD+K-)/Gamma(Xi_cc+ -> Lambda_c K- pi+) = 0.36+/-0.21.Comment: 11 pages, 6 included eps figures. v2 includes improved statistical method to determine significance of observation. Submitted to PL

Demonstration of the temporal matter-wave Talbot effect for trapped matter waves

We demonstrate the temporal Talbot effect for trapped matter waves using ultracold atoms in an optical lattice. We investigate the phase evolution of an array of essentially non-interacting matter waves and observe matter-wave collapse and revival in the form of a Talbot interference pattern. By using long expansion times, we image momentum space with sub-recoil resolution, allowing us to observe fractional Talbot fringes up to 10th order.Comment: 17 pages, 7 figure

Kaon Production and Kaon to Pion Ratio in Au+Au Collisions at \snn=130 GeV

Mid-rapidity transverse mass spectra and multiplicity densities of charged and neutral kaons are reported for Au+Au collisions at \snn=130 GeV at RHIC. The spectra are exponential in transverse mass, with an inverse slope of about 280 MeV in central collisions. The multiplicity densities for these particles scale with the negative hadron pseudo-rapidity density. The charged kaon to pion ratios are $K^+/\pi^- = 0.161 \pm 0.002 {\rm (stat)} \pm 0.024 {\rm (syst)}$ and $K^-/\pi^- = 0.146 \pm 0.002 {\rm (stat)} \pm 0.022 {\rm (syst)}$ for the most central collisions. The $K^+/\pi^-$ ratio is lower than the same ratio observed at the SPS while the $K^-/\pi^-$ is higher than the SPS result. Both ratios are enhanced by about 50% relative to p+p and $\bar{\rm p}$+p collision data at similar energies.Comment: 6 pages, 3 figures, 1 tabl

Azimuthal anisotropy and correlations in p+p, d+Au and Au+Au collisions at 200 GeV

We present the first measurement of directed flow ($v_1$) at RHIC. $v_1$ is found to be consistent with zero at pseudorapidities $\eta$ from -1.2 to 1.2, then rises to the level of a couple of percent over the range $2.4 < |\eta| < 4$. The latter observation is similar to data from NA49 if the SPS rapidities are shifted by the difference in beam rapidity between RHIC and SPS. Back-to-back jets emitted out-of-plane are found to be suppressed more if compared to those emitted in-plane, which is consistent with {\it jet quenching}. Using the scalar product method, we systematically compared azimuthal correlations from p+p, d+Au and Au+Au collisions. Flow and non-flow from these three different collision systems are discussed.Comment: Quark Matter 2004 proceeding, 4 pages, 3 figure

Azimuthal anisotropy: the higher harmonics

We report the first observations of the fourth harmonic (v_4) in the azimuthal distribution of particles at RHIC. The measurement was done taking advantage of the large elliptic flow generated at RHIC. The integrated v_4 is about a factor of 10 smaller than v_2. For the sixth (v_6) and eighth (v_8) harmonics upper limits on the magnitudes are reported.Comment: 4 pages, 6 figures, contribution to the Quark Matter 2004 proceeding