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1699 Publications visible to you, out of a total of 1699
Substituting density functional theory in reaction barrier calculations for hydrogen atom transfer in proteins

Abstract (Expand)

Hydrogen atom transfer (HAT) reactions are important in many biological systems. As these reactions are hard to observe experimentally, it is of high interest to shed light on them using simulations. … Here, we present a machine learning model based on graph neural networks for the prediction of energy barriers of HAT reactions in proteins. As input, the model uses exclusively non-optimized structures as obtained from classical simulations. It was trained on more than 17 000 energy barriers calculated using hybrid density functional theory. We built and evaluated the model in the context of HAT in collagen, but we show that the same workflow can easily be applied to HAT reactions in other biological or synthetic polymers. We obtain for relevant reactions (small reaction distances) a model with good predictive power (R2 ∼ 0.9 and mean absolute error of <3 kcal mol−1). As the inference speed is high, this model enables evaluations of dozens of chemical situations within seconds. When combined with molecular dynamics in a kinetic Monte-Carlo scheme, the model paves the way toward reactive simulations.

Authors: Kai Riedmiller, Patrick Reiser, Elizaveta Bobkova, Kiril Maltsev, Ganna Gryn’ova, Pascal Friederich, Frauke Gräter

Date Published: 14th Feb 2024

Publication Type: Journal

Reevaluating LSST’s Capability for Time Delay Measurements in Quasar Accretion Disks

Abstract (Expand)

Abstract The Legacy Survey of Space and Time at the Vera C. Rubin Observatory is poised to observe thousands of quasars using the Deep Drilling Fields (DDF) across six broadband filters over a decade. …and filters over a decade. Understanding quasar accretion disk (AD) time delays is pivotal for probing the physics of these distant objects. Pozo Nuñez et al. has recently demonstrated the feasibility of recovering AD time delays with accuracies ranging from 5% to 20%, depending on the quasar’s redshift and time sampling intervals. Here we reassess the potential for measuring AD time delays under the current DDF observing cadence, which is placeholder until a final cadence is decided. We find that contrary to prior expectations, achieving reliable AD time delay measurements for quasars is significantly more challenging, if not unfeasible, due to the limitations imposed by the current observational strategies.

Authors: F. Pozo Nuñez, B. Czerny, S. Panda, A. Kovacevic, W. Brandt, K. Horne

Date Published: 14th Feb 2024

Publication Type: Journal

Easy uncertainty quantification (EasyUQ): Generating predictive distributions from single-valued model output

Abstract

Not specified

Authors: Eva-Maria Walz, Alexander Henzi, Johanna Ziegel, Tilmann Gneiting

Date Published: 8th Feb 2024

Publication Type: Journal

Mechanical control of the adhesion of malaria-infected erythrocytes to the placenta

Abstract (Expand)

Pathogens use sophisticated adhesion mechanisms to remain attached to the host’s surfaces. A key example of this is the adhesion of erythrocytes infected with Plasmodium, the parasite which causes … malaria, to the microvasculature. Remarkably, in the case of pregnancy-associated malaria, the adherence of parasitized erythrocytes to the placenta is enhanced by the shear of the flowing blood, suggesting a catch-bond adhesion mechanism. The adhesion is mediated by a parasite protein called VAR2CSA which anchors such infected erythrocytes to the proteoglycan matrix of the placenta. In this work, by using extensive equilibrium and force-probe molecular dynamics simulations, we elucidate the—so far unknown—molecular mechanism governing the adhesive function of VAR2CSA. We demonstrate that the elongation tension that arises from the shear of the flowing blood opens VAR2CSA into two structurally-intact domains, thereby exposing cryptic sugar binding sites. The orientation of VAR2CSA with respect to the pulling direction as well as strong sugar-protein shearing interactions favor this mode of opening. Accordingly, as the basis for a catch bond, we propose that mechanical forces strengthen the adhesion of infected erythrocytes, by increasing the number of sugar binding sites in VAR2CSA and not the bond lifetime as it would be canonically thought for a catch bond. This constitutes a new intriguing hypothesis which is of high relevance for our understanding of malaria infection and for the design of vaccines. More generally, our results put forward force-induced multivalency of mechano-responsive proteins as a key new concept for pathogen-host interactions.

Authors: Rita Roessner, Nicholas Michelarakis, Frauke Gräter, Camilo Aponte-Santamaría

Date Published: 8th Feb 2024

Publication Type: Journal

T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery

Abstract (Expand)

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA–presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite … to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual’s unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER’s potency and versatility.

Authors: Miray Cetin, Veronica Pinamonti, Theresa Schmid, Tamara Boschert, Ana Mellado Fuentes, Kristina Kromer, Taga Lerner, Jing Zhang, Yonatan Herzig, Christopher Ehlert, Miguel Hernandez-Hernandez, Georgios Samaras, Claudia Maldonado Torres, Laura Fisch, Valeriia Dragan, Arlette Kouwenhoven, Bertrand Van Schoubroeck, Hans Wils, Carl Van Hove, Michael Platten, Edward W. Green, Frederik Stevenaert, Nathan J. Felix, John M. Lindner

Date Published: 2nd Feb 2024

Publication Type: Journal

Learning to forecast: The Probabilistic Time Series Forecasting Challenge

Abstract

Not specified

Authors: Johannes Bracher, Nils Koster, Fabian Krüger, Sebastian Lerch

Date Published: 1st Feb 2024

Publication Type: Journal

Comparative evaluation of point process forecasts

Abstract

Not specified

Authors: Jonas R. Brehmer, Tilmann Gneiting, Marcus Herrmann, Warner Marzocchi, Martin Schlather, Kirstin Strokorb

Date Published: 1st Feb 2024

Publication Type: Journal

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