Dynamics in unfolded polypeptide chains as model for elementary steps in protein folding

This thesis deals with the dynamics of unfolded polypeptide chains as model for the earliest steps in protein folding. Starting from an ensemble of unfolded conformations a folding polypeptide chain has to form specific backbone and side-chain interactions to reach the native state. The rate at which two defined contacts are formed on a polypeptide chain is limited by intrachain diffusion. The characterization of rate constants of intrachain contact formation in polypeptides and their dependence on length, sequence and solvent effects give new insights for an understanding of the dynamics of the earliest steps in protein folding. Until recently, little was known about absolute time scales of intramolecular contact formation in polypeptide chains. Direct measurements of fast intramolecular diffusion processes became possible with the development of fast diffusion-controlled electron transfer processes. In the presented work triplet-triplet energy transfer was used to characterize intrachain contact formation in homo-polypeptides and peptide fragments derived from natural protein sequences. The transfer of triplet electrons between the triplet donor xanthone to the triplet acceptor naphthalene is diffusion-controlled as tested by measuring its temperature and viscosity dependencies. The results suggest that triplet-triplet energy transfer from xanthone to naphthalene provides the requirement to determine absolute intramolecular contact formation rate constants in polypeptide chains. Intrachain contact formation in unstructured polypeptides is well described as a single exponential process. The loop-size dependence of the rate constants of intrachain contact formation revealed that intrachain motions over short and long distances are limited by different rate-limiting steps. In short peptide chains end-to-end contact formation is with a minimum time constant of 5-10 ns virtually independent of chain length and limited by an activation barrier of 12-16 kJ/mol. In long flexible poly(glycine-serine) peptide chains with more than twenty peptide bonds N the rate constants decrease with N-1.7±0.1 and end-to-end contact formation becomes nearly completely entropy-driven. Glycine and proline residues significantly change local intrachain dynamics compared to all other amino acids. Glycine accelerates contact formation whereas short proline containing peptides reveal complex kinetics of contact formation. Local chain dynamics are accelerated by a cis and slowed down by a trans peptidyl-prolyl bond. The effects vanish in peptide chains if the sequence contains more than five amino acids on each side of a single glycyine or a single proline residue. The dynamics of loop formation are sensitive to the nature of the solvent. Good solvents, such as denaturants slow down intrachain dynamics compared to water. The effect of solvent composition on chain dynamics indicates that the chain properties of polypeptides strongly depend on the surrounding conditions. Natural protein sequences are more complex than homo-polypeptide chains because they consist of 20 different amino acids. We determined the dynamics of loop formation in sequences derived from two proteins, carp muscle β-parvalbumin and protein G B1 domain. Compared to homo-polypeptides the intrachain dynamics in natural loop sequences are slowed down and higher activation barriers are determined. The results suggest that the dynamics of the earliest steps in protein folding are limited by significant activation barriers. The results allow us to estimate an upper time scale for rates of contact formation in unstructured peptide chains. In glycine-rich sequences, which are often found in β- hairpins and turns a first contact over 3-4 peptide bonds will be formed within 10-15 ns. For glycine-free sequences local contact formation is slowed down to 15-50 ns depending on the sequence. Due to the strong distance dependence of the rate constant of the end-to-end contact formation long-range interactions on an unfolded polypeptide chain over 50-60 peptide bonds will not be formed faster than in 500 ns

From labels to functions : how working memory capacity facilitates processing of matrix reasoning items with multiple rules

The question why some individuals are more intelligent than others is one of the most important questions of the last 100 years in psychology. This study set out to investigate why individuals are better in matrix reasoning as one of the most prominent proxies of intelligence. One well-replicated finding is that matrix-reasoning items with multiple rules are harder to solve than items with a single rule. Notably, it is assumed that the individual working memory capacity (WMC) plays a crucial role in the processing of items with multiple rules. However, it is still an ongoing question why WMC is facilitating the processing of these items. In this work, we investigated possible roles of WMC in matrix-reasoning items with multiple rules. In doing so, we experimentally manipulated certain processes in matrix reasoning which are suggested in the literature to be more demanded in items with multiple rules. In addition, we observed the impact of WMC on these processes from a functional perspective. That is to say, we defined WMC not as an overall resource, but based on the WMC-literature, we examined which aspect of WMC could be required for the respective processes in matrix reasoning. The first study investigated whether storing partial solutions is required in matrix-reasoning and whether individual storage capacity as one aspect of WMC facilitates the storing of partial solutions. The second study can be regarded as a preliminary study for the third study, which quantified the influence of filtering as a further aspect of WMC on matrix-reasoning. The third study investigated whether selective encoding demands are present in multiple-rule items by means of both behavioral and eye movement analyses. We also observed whether individual filtering ability facilitates selective encoding in matrix reasoning. In addition, we observed whether goal management demands are present in multiple-rule items and whether individual storage and processing as another aspect of WMC is related to goal management. Results of all studies revealed that neither storing partial solutions nor goal management were required in multiple rule items, nor that these demands were associated with the aspects of WMC assessed in the respective studies. In contrast, results indicate that higher difficulties in multiple-rule items were mainly due to higher demands on selective encoding and more importantly, filtering facilitated processing of items with these demands. The results of the present study entail important implications for both matrix-reasoning processing and intelligence but also for our understanding of the involvement of WMC in intelligence.Die Frage, warum manche Menschen intelligenter sind als andere, ist eine der wichtigsten Fragen der letzten 100 Jahre in der Psychologie. In dieser Studie wurde untersucht, warum einige Personen in figuralen Matrizentests – als einer der prominentesten Verfahren zu Erfassung von Intelligenz – besser sind als andere. Ein gut replizierter Befund ist, dass figuralen Matrizentest-Aufgaben mit mehreren Regeln schwieriger zu lösen sind als Aufgaben mit einer einzigen Regel. Insbesondere wird davon ausgegangen, dass die individuelle Arbeitsspeicherkapazität (WMC) eine entscheidende Rolle bei der Verarbeitung von Aufgaben mit mehreren Regeln spielt. Es ist jedoch immer noch ungeklärt, warum WMC die Bearbeitung dieser Aufgaben erleichtert. Deshalb untersuchten wir in dieser Arbeit mögliche Einflüsse von WMC in figuralen Matrizentest mit mehreren Regeln. Hierbei manipulierten wir experimentell bestimmte Prozesse in figuralen Matrizentests, die in der Literatur als wichtige Prozess diskutiert werden, die bei Aufgaben mit mehreren Regeln stärker beansprucht zu sein scheinen. Darüber hinaus beobachteten wir den funktionalen Einfluss von WMC auf diese Prozesse. Das heißt, wir haben WMC nicht als Gesamtressource definiert, sondern auf der Grundlage der Literatur untersucht, welcher Aspekt von WMC für die jeweiligen Prozesse in figuralen Matrizentests benötigt werden könnte. Die erste Studie untersuchte, ob die Speicherung von Teillösungen in figuralen Matrizentest erforderlich ist und ob die individuelle Speicherkapazität, als Teilaspekt von WMC, die Speicherung von Teillösungen erleichtert. Die zweite Studie kann als Vorstudie für die dritte Studie betrachtet werden, die den Einfluss der Filterfähigkeit als weiteren Aspekt von WMC auf figural Matrizentests quantifizierte. Die dritte Studie untersuchte anhand von Verhaltens- und Augenbewegungsanalysen, ob selektive Enkodierungsanforderungen in Aufgaben mit mehreren Regeln vorhanden sind. Wir beobachteten zudem, ob individuelle Filterfähigkeiten das selektive Enkodieren in figuralen Matrizentests erleichtert. Darüber hinaus beobachteten wir, ob Anforderungen an das Zielmanagement in Aufgaben mit mehreren Regeln vorhanden sind und ob die Fähigkeit Inhalte im Arbeitsgedächtnis während der Bearbeitung einer kompetitiven Zeitaufgabe zu speichern mit dem Zielmanagement zusammenhängt. Die Ergebnisse der Studien zeigen, dass weder die Speicherung von Teillösungen noch das Zielmanagement in Aufgaben mit mehreren Regeln erforderlich war, noch, dass diese Anforderungen mit den jeweiligen Aspekten des WMC, die in den jeweiligen Studien erhoben wurde, zusammenhing. Im Gegensatz deuten die Ergebnisse darauf hin, dass höhere Schwierigkeiten bei Aufgaben mit mehreren Regeln hauptsächlich auf höhere Anforderungen an die selektive Enkodierung zurückzuführen waren, und was noch wichtiger ist, die Filterfähigkeit das Lösen dieser Aufgaben erleichterte. Die Ergebnisse der vorliegenden Studie beinhalten wichtige Implikationen sowohl für die Verarbeitung von figuralen Matrizentests als auch für Intelligenz im Allgemeinen, aber auch für unser Verständnis über die Beteiligung von WMC an Intelligenz.This research was conducted within the International Research Training Group "Adaptive Minds" supported by German Research Foundation (DFG) under Grant 1457

Delayed development of basic numerical skills in children with developmental dyscalculia

Research suggests that children with developmental dyscalculia (DD) have deficits in basic numerical skills. However, there is conflicting evidence on whether basic numerical skills in children with DD are qualitatively different from those in typically developing children (TD) or whether basic numerical skills development in children with DD is simply delayed. In addition, there are also competing hypotheses about deficits in basic numerical skills, assuming (1) a general deficit in representing numerosities (Approximate Number System, ANS), (2) specific deficits in an object-based attentional system (Object Tracking System, OTS), or (3) deficits in accessing numerosities from symbols (Access Deficit, AD). Hence, the purpose of this study was to investigate whether deficits in basic numerical skills in children with DD are more indicative of a developmental delay or a dyscalculia-specific qualitative deviation and whether these deficits result from (selective) impairment of core cognitive systems involved in numerical processing. To address this, we tested 480 children (68 DD and 412 TD) in the 2nd, 3rd, and 4th grades with different paradigms for basic numerical skills (subitizing, counting, magnitude comparison tasks, number sets, and number line estimation tasks). The results revealed that DD children’s impairments did not indicate qualitatively different basic numerical skills but instead pointed to a specific developmental delay, with the exception of dot enumeration. This result was corroborated when comparing mathematical profiles of DD children in 4th grade and TD children in 2nd grade, suggesting that DD children were developmentally delayed and not qualitatively different. In addition, specific deficits in core markers of numeracy in children with DD supported the ANS deficit rather than the AD and OTS deficit hypothesis