The Conformism of K. P. Pobedonostsev’s Parish Reform

The article was submitted on 10.05.2014.The article is devoted to the measures taken by chief procurator of the Holy Synod Konstantin Pobedonostsev between the 1880s–1890s and aimed at the reduction of the severity “of the parish question” in the Russian Empire. The measures included the revision of the parish reforms of the epoch of Great reforms, resulting in a parish counter-reform. It introduced the policy abolishing the enlargement of parishes, which was supported by the episcopate. It also included an unachieved attempt to change The Regulations of the Parish Wards in Orthodox Churches (1864). A new edition of The Instruction to the Church (Parish) Elders was published at that time, and new attempts were made to solve the issue of material support of the clergy, primarily through the introduction of a government salary. The author agrees that in his parish reform K. P. Pobedonostsev was maneuvering between different social forces, especially between the bishops and the active zemstvo members, trying to make concessions to both, but not changing anything substantially. As a result, his “reform” consisting of halfmeasures was not only incomplete, but, in fact, could not enhance the life of the parish and therefore met the challenges of the time.Рассматривается комплекс мероприятий 1880–1890-х гг. обер-прокурора Святейшего синода К. П. Победоносцева, направленных на снижение остроты «приходского вопроса» в Российской империи. Часть этих мероприятий представляла собой ревизию приходских преобразований эпохи Великих реформ, своего рода приходскую контрреформу. В их числе были поддержанный епископатом отказ от политики укрупнения приходов, а также незавершенная попытка изменения Положения о приходских попечительствах при православных церквах 1864 г. Кроме того, в этот период была издана новая редакция Инструкции церковным (приходским) старостам и предприняты новые попытки решения вопроса материального обеспечения духовенства, прежде всего путем введения казенного жалованья. Автор солидаризуется с той точкой зрения, что К. П. Победоносцев, проводя свою «приходскую реформу», лавировал между различными общественными силами, в первую очередь между епископатом и активными земцами, стремясь сделать уступки тем и другим, не меняя ничего по существу. На основе анализа свода постановлений и законов, а также архивных материалов делается вывод о том, что его реформа не только осталась незавершенной, но и не могла в принципе активизировать жизнь прихода, а значит, и ответить на вызовы времени

How proteins bind macrocycles

The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product-derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.R01 GM094551 - NIGMS NIH HHS; GM064700 - NIGMS NIH HHS; GM094551 - NIGMS NIH HHS; R01 GM064700 - NIGMS NIH HHS; GM094551-01S1 - NIGMS NIH HH

Efficient maintenance and update of nonbonded lists in macromolecular simulations

Molecular mechanics and dynamics simulations use distance based cutoff approximations for faster computation of pairwise van der Waals and electrostatic energy terms. These approximations traditionally use a precalculated and periodically updated list of interacting atom pairs, known as the “nonbonded neighborhood lists” or nblists, in order to reduce the overhead of finding atom pairs that are within distance cutoff. The size of nblists grows linearly with the number of atoms in the system and superlinearly with the distance cutoff, and as a result, they require significant amount of memory for large molecular systems. The high space usage leads to poor cache performance, which slows computation for large distance cutoffs. Also, the high cost of updates means that one cannot afford to keep the data structure always synchronized with the configuration of the molecules when efficiency is at stake. We propose a dynamic octree data structure for implicit maintenance of nblists using space linear in the number of atoms but independent of the distance cutoff. The list can be updated very efficiently as the coordinates of atoms change during the simulation. Unlike explicit nblists, a single octree works for all distance cutoffs. In addition, octree is a cache-friendly data structure, and hence, it is less prone to cache miss slowdowns on modern memory hierarchies than nblists. Octrees use almost 2 orders of magnitude less memory, which is crucial for simulation of large systems, and while they are comparable in performance to nblists when the distance cutoff is small, they outperform nblists for larger systems and large cutoffs. Our tests show that octree implementation is approximately 1.5 times faster in practical use case scenarios as compared to nblists

Encounter complexes and dimensionality reduction in protein-protein association

An outstanding challenge has been to understand the mechanism whereby proteins associate. We report here the results of exhaustively sampling the conformational space in protein–protein association using a physics-based energy function. The agreement between experimental intermolecular paramagnetic relaxation enhancement (PRE) data and the PRE profiles calculated from the docked structures shows that the method captures both specific and non-specific encounter complexes. To explore the energy landscape in the vicinity of the native structure, the nonlinear manifold describing the relative orientation of two solid bodies is projected onto a Euclidean space in which the shape of low energy regions is studied by principal component analysis. Results show that the energy surface is canyon-like, with a smooth funnel within a two dimensional subspace capturing over 75% of the total motion. Thus, proteins tend to associate along preferred pathways, similar to sliding of a protein along DNA in the process of protein-DNA recognition

Discovery of macrocyclic inhibitors of apurinic/apyrimidinic endonuclease 1

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.This work was supported by grants from the National Institutes of Health (Grant R01CA205166 to M.R.K. and M.M.G. and Grant R01CA167291 to M.R.K.) and by the Earl and Betty Herr Professor in Pediatric Oncology Research, Jeff Gordon Children's Foundation, and the Riley Children's Foundation (M.R.K.). Work at the BU-CMD (J.A.P., L.E.B., R.T.) is supported by the National Institutes of Health, Grant R24 GM111625. D.B. and S.V. were supported by the National Institutes of Health, Grant R35 GM118078. (R35 GM118078 - National Institutes of Health; R01CA205166 - National Institutes of Health; R01CA167291 - National Institutes of Health; R24 GM111625 - National Institutes of Health; Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children's Foundation; Riley Children's Foundation)Accepted manuscriptSupporting documentatio

Theory of short-term and long-term resistance of structures based on the principle of plastic fracture

The authors analyze the theory used in many countries, containing two independent directions: 1) the theory of stability of rod systems, including flat frames; 2) the theory of calculation of structural elements from various materials. The main feature of these theories is the application of the principle of plastic fracture. The assumption about a plastic hinge, due to the inconsistency with the experimental data, is supplemented by the incorrect application of theories of infinite elastic deformations, as well as of infinite creep deformations, which are incompatible with this hinge. Using the rules of mathematics, the principles of mechanics and the results of reliable experiments, it has been revealed that the analyzed theory contains several theories for different applications that reject each other, including the erroneous ones

Docking Server for the Identification of Heparin Binding Sites on Proteins

Many proteins of widely differing functionality and structure are capable of binding heparin and heparan sulfate. Since crystallizing protein–heparin complexes for structure determination is generally difficult, computational docking can be a useful approach for understanding specific interactions. Previous studies used programs originally developed for docking small molecules to well-defined pockets, rather than for docking polysaccharides to highly charged shallow crevices that usually bind heparin. We have extended the program PIPER and the automated protein–protein docking server ClusPro to heparin docking. Using a molecular mechanics energy function for scoring and the fast Fourier transform correlation approach, the method generates and evaluates close to a billion poses of a heparin tetrasaccharide probe. The docked structures are clustered using pairwise root-mean-square deviations as the distance measure. It was shown that clustering of heparin molecules close to each other but having different orientations and selecting the clusters with the highest protein–ligand contacts reliably predicts the heparin binding site. In addition, the centers of the five most populated clusters include structures close to the native orientation of the heparin. These structures can provide starting points for further refinement by methods that account for flexibility such as molecular dynamics. The heparin docking method is available as an advanced option of the ClusPro server at http://cluspro.bu.edu/

Extracellular Blockade of K+ Channels by Tea: Results from Molecular Dynamics Simulations of the Kcsa Channel

TEA is a classical blocker of K+ channels. From mutagenesis studies, it has been shown that external blockade by TEA is strongly dependent upon the presence of aromatic residue at Shaker position 449 which is located near the extracellular entrance to the pore (Heginbotham, L., and R. MacKinnon. 1992. Neuron. 8:483–491). The data suggest that TEA interacts simultaneously with the aromatic residues of the four monomers. The determination of the 3-D structure of the KcsA channel using X-ray crystallography (Doyle, D.A., J.M. Cabral, R.A. Pfuetzner, A. Kuo, J.M. Gulbis, S.L. Cohen, B.T. Chait, and R. MacKinnon. 1998. Science. 280:69–77) has raised some issues that remain currently unresolved concerning the interpretation of these observations. In particular, the center of the Tyr82 side chains in KcsA (corresponding to position 449 in Shaker) forms a square of 11.8-Å side, a distance which is too large to allow simultaneous interactions of a TEA molecule with the four aromatic side chains. In this paper, the external blockade by TEA is explored by molecular dynamics simulations of an atomic model of KcsA in an explicit phospholipid bilayer with aqueous salt solution. It is observed, in qualitative accord with the experimental results, that TEA is stable when bound to the external side of the wild-type KcsA channel (with Tyr82), but is unstable when bound to a mutant channel in which the tyrosine residue has been substituted by a threonine. The free energy profile of TEA relative to the pore is calculated using umbrella sampling simulations to characterize quantitatively the extracellular blockade. It is found, in remarkable agreement with the experiment, that the TEA is more stably bound by 2.3 kcal/mol to the channel with four tyrosine residues. In the case of the wild-type KcsA channel, TEA (which has the shape of a flattened oblate spheroid) acts as an ideal plug blocking the pore. In contrast, it is considerably more off-centered and tilted in the case of the mutant channel. The enhanced stability conferred by the tyrosine residues does not arise from Π–cation interactions, but appears to be due to differences in the hydration structure of the TEA. Finally, it is shown that the experimentally observed voltage dependence of TEA block, which is traditionally interpreted in terms of the physical position of the TEA along the axis of the pore, must arise indirectly via coupling with the ions in the pore