Application of computational methods for the design of BACE-1 inhibitors : validation of in silico modelling

β-Secretase (BACE-1) constitutes an important target for search of anti-Alzheimer’s drugs. The first inhibitors of this enzyme were peptidic compounds with high molecular weight and low bioavailability. Therefore, the search for new efficient non-peptidic inhibitors has been undertaken by many scientific groups. We started our work from the development of in silico methodology for the design of novel BACE-1 ligands. It was validated on the basis of crystal structures of complexes with inhibitors, redocking, cross-docking and training/test sets of reference ligands. The presented procedure of assessment of the novel compounds as β-secretase inhibitors could be widely used in the design process

Structural bioinformatics of membrane proteins

Our genome is composed of 20-30 % of membrane proteins but number of structures of these proteins known and deposited in public databases is still small. However, new achievements in experimental techniques, especially microfocusing of X-ray beam enabling diffracting of microcrystals, as well as mutagenesis leading to obtaining of thermostable mutants are real hope for quick emerging of new structures. Theoretical methods for determination of structure of membrane proteins are still in infant phases. Usage of homology modeling is limited by small number of membrane proteins which are necessary to serve as templates whereas ab-initio methods are confined to predicting of small membrane proteins or parts of larger ones only. The area which the bioinformatics is foremost in is prediction of dynamical behavior of proteins in lipid bilayer which is still mostly inaccessible to experimental methods. Full-atom as well as coarse-grain molecular dynamics methods are used to describe investigated systems in different time scales and with different accuracy

Canis lupus familiaris. The Symbolism of the Dog in History, Art and Literature: An Overview

Pies towarzyszy człowiekowi od zarania dziejów. Brał udział w polowaniach, służył jak stróż mienia, pupil do zabaw, dlatego kojarzono go z cechami pozytywnymi, takimi jak wierność, oddanie, czujność, przywiązanie. Przez wieki zyskał szereg odniesień w kulturze i sztuce, mających charakter tak pozytywny, jak i negatywny. Warto zaznaczyć, że jest on, obok kota, tym zwierzęciem, które jest obecne we wszystkich kulturach i wierzeniach od zarania dziejów po dzień dzisiejszy. Już w starożytności zyskał szczególne miejsce na dworze faraonów, a także w panteonie bogów w Egipcie czy pośród bogów greckich, jako ich towarzysz. Był obecny w życiu bogatych i biednych, wykorzystywany do różnorakich celów. Nie dziwi także bogata symbolika biblijna, która, co ciekawe, w Starym Testamencie ma znaczenie negatywne, zastąpione później wykładnią pozytywną w Nowym Testamencie, u Ojców Kościoła i w hagiografii. Pies był zatem nie tylko symbolem wierności, oddania, ofiarności i odwagi, ale też symbolem rozwiązłości, chciwości, zachłanności, wrogości, co ukazano w niniejszym wywodzie, odwołując się do różnych motywów biblijnych i artystycznych. Wierzenia ludowe podkreślają znaczenie psa w gusłach, magii, a nawet leczeniu, prezentując go jako zwierzę niezwykłe. Pojawia się on również w takich sferach, jak heraldyka, numizmatyka, sfragistyka, a także znaczki pocztowe i medale. Dzisiejsza kultura masowa wytworzyła szereg nowych odniesień do psa w filmie, literaturze, komiksie, animacji, łącząc w sobie bogactwo symboliki wypracowane przez wieki, zwłaszcza ikony wierności i oddania.The dog has accompanied humans ever since the dawn of time. It has taken part in hunting, served as a guardian of property, and as a pet for entertainment. It has been associated with positive qualities such as loyalty, devotion, vigilance and attachment. Over the centuries, it has gained a number of representations in culture and art, both positive and negative. It is worth noting that, besides the cat, it is the only animal which has appeared in all cultures and beliefs from the dawn of time down to the present day. In antiquity, it had already gained a special place in the court of the pharaohs, as well as in the pantheon of the gods in Egypt or among the Greek gods as their companion. It was present in the lives of the rich and the poor, and was used for various purposes. Not surprisingly, the rich biblical symbolism, which, interestingly, in the Old Testament, has negative overtones, was later replaced by positive interpretations in the New Testament, the writings of the Church Fathers, and hagiographies. The dog has thus been not only a symbol of fidelity, devotion, self-sacrifice and courage, but also one of licentiousness, greed and hostility, as is shown in this study, which makes reference to various biblical and artistic themes. Folk beliefs emphasise the importance of the dog in witchcraft, magic and even healing, presenting it as an unusual animal. It is also featured in such spheres as heraldry, numismatics, sphragistics, and on postage stamps and medals. Today’s mass culture has produced a number of new references to the dog in film, literature, comics and animation, all of which combine the wealth of this symbolism developed over the centuries, especially as icons of fidelity and devotion

The Network Transformation of the Polish State Functions

Znaczenie sieci w procesie transformacji funkcji państwa polskiego nie zawsze bywa docenianie. Dzieje się tak zapewne dlatego, że świadomość funkcjonowania sieci nie jest powszechna, a perspektywa sieciowa jest stosunkowo nowym, niestety wciąż słabo rozpoznawalnym narzędziem badawczym na gruncie współczesnych nauk społecznych. Eksplikacja procesu transformacji funkcji państwa polskiego niemożliwa jest tymczasem bez zrozumienia roli, jaką we współczesnym świecie odgrywają sieciowe formy komunikacji oraz organizacji. Sieci pełnią rolę platform wymiany szeroko rozumianych dóbr materialnych i niematerialnych. Podmiotami uczestniczącymi w owej wymianie są: państwa, korporacje transnarodowe, grupy przestępcze, sieci terrorystyczne, organizacje pozarządowe, globalne ruchy społeczne, a także obywatele zorganizowani w rozmaite stowarzyszenia, kluby i związki. Aktorzy ci spotykają się ze sobą na wielu przecinających się płaszczyznach, uczestnicząc zarówno w efemerycznych, jak i trwałych, jednorazowych oraz powtarzających się aktach wymian. Sieci na nowo definiują pozycję Polski w globalnej strukturze władzy. Pozycja ta jest wypadkową trzech wektorów: transformacji systemowej, integracji europejskiej oraz globalizacji. Państwo uwikłane w trzy, teleologicznie różne porządki sieciowe, traci możliwość wypełniania wielu ważnych funkcji. Warunkiem sukcesu staje się zdolność do rozpoznawania i ponownego definiowania siebie, nieustannego dostosowywania koncepcji własnej polityczności do zmiennych warunków środowiska. W przypadku Polski, chodzi o przeorientowanie instytucji państwa na realizuję funkcji regionalnych oraz globalnych. Niniejszy esej przedstawia kierunki reorganizacji funkcji państwa polskiego, a także korzyści oraz zagrożenia związane z tym procesem.The importance of networks in the transformation of the Polish state functions is underestimated. This is probably because the awareness of the network structures is not common and the network analysis is still new research tool in contemporary social science. It’s impossible to understand the transformation of the Polish state functions without understanding the role played by network forms of organization and communication. In the modern world, networks are often used as the exchange platforms enabling dynamic move of goods, ideas, values etc. Deeply involved in this exchange are: states, transnational corporations, criminal groups, terrorist networks, nongovernmental organizations, global social movements and citizens organized in various associations, clubs, and unions. All of these actors meet together on the interrelated planes, participating in ephemeral and permanent, single and repeated acts of exchange. Networks re-define the position of the Polish state in the global power structure. The new position is produced by three interlocking vectors: economic transformation in Central and Eastern Europe; European integration; and globalisation. The nation-state involved in three contradictory network realms is unable to fulfil many crucial functions. Success on the global stage depends on the ability of states to identify and redefine themselves. In case of Poland, the most urgent issue seems to be the reorientation of public institutions to implement the regional and global functions. This essay presents the directions of the reorganization of the functions of the Polish state, as well as the benefits and risks associated with this process

A Hybrid Approach to Structure and Function Modeling of G Protein-Coupled Receptors

The recent GPCR Dock 2013 assessment of serotonin receptor 5-HT_1B and 5-HT_2B, and smoothened receptor SMO targets, exposed the strengths and weaknesses of the currently used computational approaches. The test cases of 5-HT_1B and 5-HT_2B demonstrated that both the receptor structure and the ligand binding mode can be predicted with the atomic-detail accuracy, as long as the target–template sequence similarity is relatively high. On the other hand, the observation of a low target–template sequence similarity, e.g., between SMO from the frizzled GPCR family and members of the rhodopsin family, hampers the GPCR structure prediction and ligand docking. Indeed, in GPCR Dock 2013, accurate prediction of the SMO target was still beyond the capabilities of most research groups. Another bottleneck in the current GPCR research, as demonstrated by the 5-HT_2B target, is the reliable prediction of global conformational changes induced by activation of GPCRs. In this work, we report details of our protocol used during GPCR Dock 2013. Our structure prediction and ligand docking protocol was especially successful in the case of 5-HT_1B and 5-HT_2B-ergotamine complexes for which we provide one of the most accurate predictions. In addition to a description of the GPCR Dock 2013 results, we propose a novel hybrid computational methodology to improve GPCR structure and function prediction. This computational methodology employs two separate rankings for filtering GPCR models. The first ranking is ligand-based while the second is based on the scoring scheme of the recently published BCL method. In this work, we prove that the use of knowledge-based potentials implemented in BCL is an efficient way to cope with major bottlenecks in the GPCR structure prediction. Thereby, we also demonstrate that the knowledge-based potentials for membrane proteins were significantly improved, because of the recent surge in available experimental structures

Conformational Changes and Unfolding of β-Amyloid Substrates in the Active Site of γ-Secretase

Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aβ40 and Aβ42, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aβ40, indicating why trimming of this substrate is so infrequent

G protein-coupled receptors - recent advances

The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β2-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago