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Dioxygen Activation and Pyrrole α‐Cleavage with Calix[4]pyrrolato Aluminates: Enzyme Model by Structural Constraint

Abstract (Expand)

The present work describes the reaction of triplet dioxygen with the porphyrinogenic calix[4]pyrrolato aluminates to alkylperoxido aluminates in high selectivity. Multiconfigurational quantum chemical … computations disclose the mechanism for this spin-forbidden process. Despite a negligible spin–orbit coupling constant, the intersystem crossing (ISC) is facilitated by singlet and triplet state degeneracy and spin–vibronic coupling. The formed peroxides are stable toward external substrates but undergo an unprecedented oxidative pyrrole α-cleavage by ligand aromatization/dearomatization-initiated O−O σ-bond scission. A detailed comparison of the calix[4]pyrrolato aluminates with dioxygen-related enzymology provides insights into the ISC of metal- or cofactor-free enzymes. It substantiates the importance of structural constraint and element–ligand cooperativity for the functions of aerobic life.

Authors: Lukas Maximilian Sigmund, Christopher Ehlert, Markus Enders, Jürgen Graf, Ganna Gryn'ova, Lutz Greb

Date Published: 5th Jul 2021

Publication Type: Journal

A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis

Abstract (Expand)

Abstract Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the … DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra-crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention. We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic CTNNB1 mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes APC and CTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The in silico experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.

Authors: Saskia Haupt, Nils Gleim, Aysel Ahadova, Hendrik Bläker, Magnus von Knebel Doeberitz, Matthias Kloor, Vincent Heuveline

Date Published: 4th Jul 2021

Publication Type: Journal

Phylourny: Predicting the Knock-out-phase of Tournaments via Phylogenetic Methods by example of the UEFA EURO 2020

Abstract

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Authors: Ben Bettisworth, Alexandros Stamatakis

Date Published: 25th Jun 2021

Publication Type: Journal

An IMERG-based optimal extended probabilistic climatology (EPC) as a benchmark ensemble forecast for precipitation in the tropics and subtropics

Abstract

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Authors: Eva–Maria Walz, Marlon Maranan, Roderick van der Linden, Andreas H. Fink, Peter Knippertz

Date Published: 16th Jun 2021

Publication Type: Journal

A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics

Abstract

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Authors: Jonas Gossen, Simone Albani, Anton Hanke, Benjamin P. Joseph, Cathrine Bergh, Maria Kuzikov, Elisa Costanzi, Candida Manelfi, Paola Storici, Philip Gribbon, Andrea R. Beccari, Carmine Talarico, Francesca Spyrakis, Erik Lindahl, Andrea Zaliani, Paolo Carloni, Rebecca C. Wade, Francesco Musiani, Daria B. Kokh, Giulia Rossetti

Date Published: 11th Jun 2021

Publication Type: Journal

Word-Level Alignment of Paper Documents with their Electronic Full-Text Counterparts

Abstract

Not specified

Authors: Mark-Christoph Müller, Sucheta Ghosh, Ulrike Wittig, Maja Rey

Date Published: 11th Jun 2021

Publication Type: InProceedings

Brownian Dynamics Simulations of Proteins in the Presence of Surfaces: Long-Range Electrostatics and Mean-Field Hydrodynamics

Abstract

Not specified

Authors: Martin Reinhardt, Neil J. Bruce, Daria B. Kokh, Rebecca C. Wade

Date Published: 8th Jun 2021

Publication Type: Journal

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