Knowledge-based Optimization of Protein-Ligand-Complex Geometries

The aim of this work was to develop a tool to optimize insilico generated protein-ligand complexes according to DrugScore (DS) potentials. DS is typically used to rescore ligand geometries that were generated by docking. Thus, these poses are optimized according to the scoring function used by the selected docking algorithm. Applying DS to such a geometry does not necessarily guarantee reliable and relevant scoring. Considering the steepness of the DS potentials, even small variations in the atomic positions can lead to large differences in the resulting scores. Thus, a local optimization with respect to DS is strongly recommended in this case. In 2009, O’Boyle et al. stated, that a local optimization is always constrained to the energy well on the potential surface in which the original pose resides. So there may be even deeper wells nearby which are not considered in the local optimization but would be equally valid. The new tool MiniMuDS, developed in this thesis, should account for this problem. On the other hand, MiniMuDS is not intended to perform a global optimization since this would, at the end, result in a new docking algorithm. Instead, the new algorithm is supposed to stay close to the pose generated by the original docking engine and simply adapts it to the DS function, a task typically addressed by local search methods. MiniMuDS was to combine these two tasks by avoiding a strictly local optimization without extending to a fully global search at the same time. Therefore, a strategy was implemented, that contains elements of a global optimization, but is still restricted to a local part of the search space. Simply speaking, the applied algorithm can overcome small hills on the potential surface, but only if the following valley is deeper than the current one. Thus, major energetic barriers between basically different conformations will not be passed. In the validation of MiniMuDS several important properties were shown: 1. The optima of the applied energy model correspond impressively well to the experimentally determined native states of the evaluated complexes. This was shown by the optimization of the original crystal structures, which resulted in an average rmsd of about 0.5Å, a value much smaller than the one observed in case of in-silico generated geometries. This deviation has to be seen in light of the positional accuracy estimated for experimental structure determination. The observed deviations virtually fall into the same range. 2. The aim of conserving the given binding modes was achieved. The presented method allows for modifications up to 2Å rmsd compared to the input geometry. Remarkably, not even 5% of the optimized docking poses fully exploited this available space. On average a modified geometry shows an rmsd of about 1Å to the input structure. 3. MiniMuDS improves a given docking solution by about 0.1Å on average. The best performance was observed for well docked poses between 1 and 2Å rmsd which could be improved by up to 0.3Å on average. 4. It was shown that an optimization exceeding the restrictions of a strictly local search can improve the resulting ranking. Up to 4.7% better success rates at a 2Å cutoff and an improvement of up to 9.3% at the 1Å level were received when comparing MiniMuDS to a local optimization. 5. Taking into account not only the top ranked solution but the whole ranking, it was shown that MiniMuDS strongly improves the discrimination between near-native and misplaced poses. Geometries with lower rmsd values to the crystal structure are more likely to be placed within the first positions of the ranking. 6. The inclusion of additional flexible components into the optimization is easy to manage while results can strongly benefit. This was shown using the example of protein side chain flexibility and binding relevant water molecules. 7. Considering computational efforts, it was shown that it is sufficient to only subject the 10 top-ranked docking solutions to an optimization. This consistently yielded slightly better ranking results for all applied protocols compared to an optimization of all generated docking solutions. At 80% less computational effort, up to 4.7% higher success rates at 2Å and 2.1% higher once at a 1Å cutoff were recorded. Especially the last aspect confirms that it is advisable to focus only on those docking poses that were already ranked high by another scoring function. This way, only poses that score well with respect to two different scoring functions are considered, taking thereby advantage of some kind of consensus effect. In light of these findings, the usage of at least a local optimization has to be strongly recommend before applying DS for rescoring purposes. Beyond that, the application of a more sophisticated search strategy like the one implemented in MiniMuDS is suggested. In particular, when dealing with small, lead-like structures, the presented method showed to substantially improve the results

Löcher bohren, Dächer bauen. Fachkonferenz "Perspektiven der Jugendsprachforschung” in Zürich, 17.-19.02.2005

Seit 13 Jahren treffen sich die VertreterInnen der germanistischen und zunehmend auch der internationalen Jugendsprachforschung in regelmäßigen Abständen zu einem Austausch über den gegenwärtigen Stand der Forschung. Nach den Fachkonferenzen in Leipzig (1992), Heidelberg (1997), Osnabrück (1998) und Wuppertal (2001) fand im Februar 2005 die fünfte Tagung in Boldern bei Zürich und damit erstmals außerhalb Deutschlands statt. Etwa 90 TeilnehmerInnen aus 15 Ländern waren der Einladung von Christa Dürscheid (Zürich) gefolgt, "neue Blicke durch alte Löcher" und "neue Blicke durch neue Löcher" zu werfen, wie es in ihrem Eröffnungsvortrag in Anlehnung an Georg Christoph Lichtenberg hieß. Neben aktuellen Ergebnissen standen also auch alte, ungelöste Grundsatzfragen der Forschung (Welchen ontologischen Status räumt man "Jugendsprache" ein? Ist sie eine Varietät, ein Stil, ein Register? Ist "Jugend" eher eine soziale oder eher eine biologische Kategorie? u. a.) auf dem Program

Organizational survey response: previous findings and an integrative framework

"This chapter discusses nonresponse to organizational surveys focusing on methodological and theoretical issues related to nonresponse. The first section provides an overview of methodologies for the study of nonresponse, including archival databases, the wave approach, the follow-up approach, and population profiling, as well as a discussion of methodological challenges in nonresponse research. The second section summarizes previous nonresponse research by examining demographics, attitudes, and organizational and survey characteristics as antecedents of nonresponse. The third section provides an integrated framework for the study of survey response. Building on previous research, we develop a model that posits several mechanisms that explain why nonresponse occurs. This model incorporates multiple levels of analysis and acknowledges the role of individual differences and situational characteristics on nonresponse behavior. In addition, we also discuss the future of nonresponse research by exploring the role of narrow personality traits, advances in technology, and organizational and national culture in survey nonresponse." (author's abstract

Sprachkritik – Eine unlösbare Aufgabe? Ergebnisse einer Befragung unter Linguisten

Während Sprachkritik in der Öffentlichkeit derzeit wieder einen (nicht unbedenklichen) Popularitätsschub erlebt, ist es innerhalb der Linguistik um das Thema seltsam still geworden. Nach den vielversprechenden Ansätzen in den Achtzigerjahren, sie als linguistische Methode zu etablieren, spielt Sprachkritik derzeit – wenn überhaupt – nur noch als Objekt eine Rolle. Ist das Unterfangen, Sprachkritik als linguistische Methode, als Form »angewandter Linguistik« innerhalb des Fachs zu etablieren, gescheitert, bevor es ein methodisches Fundament erhalten konnte? Dieser Frage gehen eine Reihe von Doktorandinnen und Doktoranden und Studierenden an der Freiburger Universität seit dem Wintersemester 2000/2001 innerhalb eines Arbeitskreises nach. In diesem Zusammenhang entstand die Idee, Vertreter der Sprachwissenschaft nach ihrer Meinung zum Thema Sprachkritik direkt zu befragen. Die Ergebnisse dieser Befragung sollen im Folgenden kurz vorgestellt werden

Digital Innovation Culture: A Systematic Literature Review

Digitalization increases the pressure for companies to innovate. While current research on digital transformation mostly focuses on technological and management aspects, less attention has been paid to organizational culture and its influence on digital innovations. The purpose of this paper is to identify the characteristics of organizational culture that foster digital innovations. Based on a systematic literature review on three scholarly databases, we initially found 778 articles that were then narrowed down to a total number of 23 relevant articles through a methodical approach. After analyzing these articles, we determine nine characteristics of organizational culture that foster digital innovations: corporate entrepreneurship, digital awareness and necessity of innovations, digital skills and resources, ecosystem orientation, employee participation, agility and organizational structures, error culture and risk-taking, internal knowledge sharing and collaboration, customer and market orientation as well as open-mindedness and willingness to learn

Value of Old Medical Books

Ovim se člankom željelo ukazati na vrijednost starog knjižnog fonda. Vrijednost starih knjiga s područja medicine ne nalazi se zbog davne godine izdavanja već u tome što su one potrebne svima koji se bave proučavanjem povijesti medicine, psihijatrije, razvojem dijagnostike i svime što je vezano uz takva istraživanja. Knjige koje su dio fonda Stručne knjižnice Klinike za psihijatriju Vrapče i koje su kratko opisane nose u sebi znanja koja su nekada bila originalna i nova. Danas, iako su ta znanja zastarjela, ne smije ih se zaboraviti jer ona čine dio medicinske teorije. Briga o starom bibliotečnom fondu ne smatra se samo općom kulturom već je ona i osnovna zadaća svake biblioteke. Stare knjige potrebno je čuvati i doživljavati kao nasljeđe i svjedočanstvo gotovo stočetresetogodišnje povijesti Klinike za psihijatriju Vrapče.The aim of this article is to bring attention to the older books of our library fund. The importance of old medical books does not lie merely in their original date of publishing but in their worth to all those interested in the history of medicine, psychiatry, development of diagnostics and everything related to such research. The old books that are part of the library collection of the Vrapče University Psychiatric Hospital, which will be briefly described, contain knowledge that was new at the time of their original publishing. Today, although the ideas in these books may seem old and dated, we must not forget that much of the knowledge they contain is part of current medical theories. Caring for the book collection of the library is not only a matter of general culture but also one of the basic tasks and duties of any library. Old copies of books and sometimes the library collection as a whole are part of a cultural legacy, because every book tells a story. Old books must be cared for and treated as part of the heritage and testimony of the one-hundred-forty-year-old history of our University Hospital

Metapragmatik, Indexikalität, soziale Registrierung: zur diskursiven Konstruktion sprachideologischer Positionen

Der vorliegende Beitrag stellt eine Variante der sprachwissenschaftlichen Diskursanalyse vor, die sowohl in der Germanistischen Diskurslinguistik als auch in der interdisziplinären Diskursforschung bislang wenig bekannt ist: Die soziolinguistische Sprachideologieforschung bzw. Metapragmatik. Der Beitrag stellt die zentralen Konzepte dieses Ansatzes vor, zeigt, wie die diskursive Aushandlung von (kommunikativen) Ideologien und die Verfestigung ideologischer Konzepte damit analysiert und modelliert wird, diskutiert soziopragmatische Funktionen von Sprachideologien und exemplifiziert die theoretischen und methodischen Erläuterungen an einem linguistischem Fallbeispiel: der Erfindung der ›Internetsprache‹ als diskursiv-interpretativem Phänomen

Degradation of glutathione in Aspergillus nidulans — Short communication

Relative transcriptions of Aspergillus nidulans dug1-3 (orthologes of Saccharomyces cerevisiae DUG — deficient in utilization of glutathione — pathway genes) and ggtA encoding γ-glutamyl transpeptidase were studied under conditions inducing glutathione degradation. GgtA was induced in all cases when glutathione levels decreased, but addition of yeast extract, which moderated glutathione degradation, enhanced its induction. Although dug2 showed constitutive transcription, dug1 and dug3 were induced by carbon and nitrogen starvation and yeast extract did not caused significant changes in their relative transcription. The in silico reconstructed DUG pathway of A. nidulans is a promising candidate for cytosolic GSH degradation induced by carbon/nitrogen stress