1,384 research outputs found
A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction
No full textThe interactions of intrinsically disordered proteins (IDPs) with their molecular targets are essential for the regulation of many cellular processes. IDPs can perform their functions while disordered, and they may fold to structured conformations on binding. Here we show that the cis/trans isomerization of peptidyl-prolyl bonds can have a pronounced effect on the interactions of IDPs. By single-molecule spectroscopy, we identify a conserved proline residue in NCBD (the nuclear-coactivator binding domain of CBP) whose cis/trans isomerization in the unbound state modulates the association and dissociation rates with its binding partner, ACTR. As a result, NCBD switches on a time scale of tens of seconds between two populations that differ in their affinities to ACTR by about an order of magnitude. Molecular dynamics simulations indicate as a cause reduced packing of the complex for the cis isomer. Peptidyl-prolyl cis/trans isomerization may be an important previously unidentified mechanism for regulating IDP interactions
A Proline Switch Explains Kinetic Heterogeneity in a Coupled Folding and Binding Reaction
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John Spaghotte
No full textAuthor Peter Schuler discusses his thoughts on how ideas of creativity, literature, and pedagogy helped to develop into his first novel, John Spaghotte of Crumb. Schuler is a native of the Coachella Valley in Southern California and writes from a middle-class appreciation of working and living in an area where everything is catered to the wealthy class. Through personal injury and his experience in undergraduate and graduate studies he fought to develop a healthy critical mind and a grasp as to the true nature of identity. As a result, his riveting debut novel about a young, nerdy California version of Don Quixote becomes a cautionary tale about the dangers of failing to recognize oneself among a world full of materialistic pleasures and grandiose, fictional heroes. In the formulation of his novel Schuler argues that artistic creation, appreciation, study, and the development of a critical scope to see the world with lead to a better understand his own identity while his protagonist suffers from the lack of such a development
Dataset for Stimulus-specific plasticity in human visual gamma-band activity and functional connectivity
No full textPer-trial dataset accompanying the publication Stauch, Peter, Schuler, and Fries (2020): Stimulus-specific plasticity in human visual gamma-band activity and functional connectivit
Daily Reflections (Meditations) on the Scriptures from the Roman Catholic Lectionary.
No full text|Who is My Neighbor?|"He lifted him up on his own animal, took him to an inn, and cared for him." (Luke 10: 34)|The scholar was clever. He posed questions that might embellish his self-regard. Jesus told a story so that the wise man could recognize the answer himself. No tribe or religion or border defines my neighbor. When I look up from my daily hustle and listen, the lives of others come closer and compassion stirs. When I hurry to the far side of the road, indifference wins again.|John Kavanaugh, S.J., author of Following Christ in a Consumer Society, wrote that we all inhabit a gospel that reveals who we are. In capitalist society, the reigning gospel measures worth by what we produce, consume, and possess. People without money, jobs, health, home, education, or status do not count for much. Paul warns that a false gospel is a curse. To measure life solely this way smothers us in emptiness.|The Samaritan was an outsider. He was familiar with insults: people moving away to avoid contact. No surprise that a person at home on the margins would notice a stranger sprawled in a ditch. Privilege had not compromised his vision. He could see. He could hear. He was moved to act.|Transformation often begins with those whose flesh touches our own. No wonder that the poor often open their doors to those in trouble. Up close, suffering and injustice become real. As our moral imagination grows, the situation of those at a distance become visible. When children fleeing violence show up at our border, we must find ways to help. God says: you will find me in the poor. That road will lead us home
Kinetics of Intramolecular Contact Formation in a Denatured Protein
No full textQuenching of the triplet state of tryptophan by cysteine has provided a
new tool for measuring the rate of forming a specific intramolecular contact
in disordered polypeptides. Here, we use this technique to investigate
contact formation in the denatured state of CspTm, a small cold-shock
protein from Thermotoga maritima, engineered to contain a single tryptophan
residue (W29) and a single cysteine residue at the C terminus
(C67). At all concentrations of denaturant, the decay rate of the W29
triplet of the unfolded protein is more than tenfold faster than the rate
observed for the native protein (10^4 1/s). Experiments on the unfolded
protein without the added C-terminal cysteine residue show that this faster
rate results entirely from contact quenching by C67. The quenching
rate in the unfolded state by C67 increases at concentrations of denaturant
that favor folding, indicating a compaction of the unfolded protein as
observed previously in single-molecule Forster resonance energy transfer
(FRET) experiments
Structural heterogeneity and quantitative FRET efficiency distributions of polyprolines through a hybrid atomistic simulation and Monte Carlo approach
No full textFörster Resonance Energy Transfer (FRET) experiments probe molecular distances via distance dependent energy transfer from an excited donor dye to an acceptor dye. Single molecule experiments not only probe average distances, but also distance distributions or even fluctuations, and thus provide a powerful tool to study biomolecular structure and dynamics. However, the measured energy transfer efficiency depends not only on the distance between the dyes, but also on their mutual orientation, which is typically inaccessible to experiments. Thus, assumptions on the orientation distributions and averages are usually made, limiting the accuracy of the distance distributions extracted from FRET experiments. Here, we demonstrate that by combining single molecule FRET experiments with the mutual dye orientation statistics obtained from Molecular Dynamics (MD) simulations, improved estimates of distances and distributions are obtained. From the simulated time-dependent mutual orientations, FRET efficiencies are calculated and the full statistics of individual photon absorption, energy transfer, and photon emission events is obtained from subsequent Monte Carlo (MC) simulations of the FRET kinetics. All recorded emission events are collected to bursts from which efficiency distributions are calculated in close resemblance to the actual FRET experiment, taking shot noise fully into account. Using polyproline chains with attached Alexa 488 and Alexa 594 dyes as a test system, we demonstrate the feasibility of this approach by direct comparison to experimental data. We identified cis-isomers and different static local environments as sources of the experimentally observed heterogeneity. Reconstructions of distance distributions from experimental data at different levels of theory demonstrate how the respective underlying assumptions and approximations affect the obtained accuracy. Our results show that dye fluctuations obtained from MD simulations, combined with MC single photon kinetics, provide a versatile tool to improve the accuracy of distance distributions that can be extracted from measured single molecule FRET efficiencies
Ensino de Arithmetica – parte theorica: um livro do padre jesuíta Luiz Schuler do início do século XX
No full textThe theme of this article is part of the History of Mathematical Education. It is a qualitative and documentary study, supported by Bardin's content analysis, to approach an arithmetic book written by Jesuit priest Luiz Schuler, published in 1904. The German Schuler circulates through schools of the Order of the Jesuits in southern Brazil, teaching Mathematics, Philosophy and Languages. He authored four books on arithmetic and one on algebra. The book Teaching of Arithmetic - theory part - covers: whole numbers, fractions, powers and roots, measures, ratios and proportions, applications of proportions - rule of three, interest, discounts and proportional division - progressions, logarithms, mixing rule and alloy and exchange. The author presents this mathematical knowledge in a theoretical way, through definitions and examples, without proposing the resolution of exercises. The mathematical knowledge is contextualized in the study units that involve applications of proportions, through problem situations related to the students' experience, highlighting the commercial context of the time, but in a reduced way, as it is a compendium that excels in concepts and procedures calculation.O tema deste artigo se insere na História da Educação Matemática. É um estudo qualitativo e documental, amparado na análise de conteúdo de Bardin, para abordagem de um livro de aritmética escrito pelo padre jesuíta Luiz Schuler, publicado no ano de 1904. O alemão Schuler circula por colégios da Ordem dos jesuítas no sul do Brasil, lecionando Matemática, Filosofia e Línguas. Foi autor de quatro livros de aritmética e um de álgebra. O livro Ensino de Arithmetica – parte theorica – aborda: números inteiros, frações, potências e raízes, medidas, razões e proporções, aplicações das proporções – regra de três, juro, descontos e divisão proporcional – progressões, logaritmos, regra de mistura e liga e câmbio. O autor apresenta esses conhecimentos matemáticos de forma teórica, por meio de definições e de exemplos, sem propor a resolução de exercícios. O conhecimento matemático está contextualizado nas unidades de estudo que envolvem aplicações das proporções, através de situações problemas relacionadas com a vivência dos estudantes, destacando o contexto comercial da época, mas de forma reduzida, pois se trata de um compêndio que prima por conceitos e procedimentos de cálculo.
Palavras-chave: História da Educação Matemática; jesuítas; aritmética; análise de conteúdo
Local and global dynamics in intrinsically disordered synuclein.
No full textIntrinsically disordered proteins experience a diverse spectrum of motions that are difficult to characterize with a single experimental technique. Here we combine high- and low-field nuclear spin relaxation, nanosecond fluorescence correlation spectroscopy (nsFCS) and long molecular dynamics simulations of alpha-synuclein, a paradigmatic IDP involved in Parkinson disease, to obtain a comprehensive picture of its conformational dynamics. The combined analysis shows that fast motions below 2 ns caused by local dihedral angle fluctuations and conformational sampling within and between Ramachandran substates decorrelate most of the backbone N-H orientational memory. However, slow motions with correlation times of up to ~13 ns from segmental dynamics are present throughout the alpha-synuclein chain, in particular in its C-terminal domain, and global chain reconfiguration occurs on a timescale of ~ 60 ns. Our study demonstrates that the combination of high- and low-field nuclear spin relaxation together with nsFCS and molecular dynamics simulations is a powerful strategy to determine residue-specific protein dynamics in IDPs at different time and length scales
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