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Allosteric communication between non-contacting sites in proteins plays a fundamental role in biological regulation and drug action. While allosteric gain-of-function variants are known drivers of onc...

Variant effect prediction remains a key challenge to resolve in precision medicine. Sophisticated computational models that exploit sequence conservation and structure are increasingly successful in t...

Here, the authors implement molecular dynamics simulations to model ATP-driven enzymatic reactions, revealing how the enzyme CK1δ phosphorylates condensates of the neurodegeneration linked protein TDP...

Building on the success of the 2022 EMBO Workshop “When Predictions Meet Experiments: The Future of Structure Determination”, this second edition continues the journey at the interface of computation…

Pathogens exploit host cellular machinery through protein-protein interactions (PPIs), often using molecular mimicry to hijack host cellular processes. While there have been thousands of host-pathogen...

Phosphorylation forms an important part of the signalling system that cells use for decision making and regulation of processes such as cell division …

Motivation: In recent years, tremendous advances have been made in predicting protein structures and protein-protein interactions. However, progress in predicting the structure of RNA, either alone or...

We are looking for exceptional early-career scientists conducting computational research with a proven record of accomplishment. The primary focus of this call is on candidates proposing research on b...

The accurate description and subsequent modeling of protein interactomes require quantification of their affinities at the proteome-wide scale. Here we develop and validate the Holdup Multiplex, a versatile assay with a mass spectrometry (MS) readout for profiling the affinities of a protein for large pools of peptides. The method can precisely quantify, in one single run, thousands of affinity constants over several orders of magnitude. The throughput, dynamic range, and sensitivity can be pushed to the performance limit of the MS readout. We applied the Holdup Multiplex to quantify in a few sample runs the affinities of the 14–3–3s, phosphoreader proteins highly abundant in humans, for 1000 different phosphopeptides. The seven human 14–3–3 isoforms were found to display similar specificities but staggered affinities, with 14–3–3γ being always the best binder and 14–3–3ε and σ being the weakest. Hundreds of new 14–3–3 binding sites were identified. We also identified dozens of 14–3–3 binding sites, some intervening in key signaling pathways, that were either stabilized or destabilized by the phytotoxin Fusicoccin-A. The results were corroborated by X-ray crystallography. Finally, we demonstrated the transferability of the Holdup Multiplex by quantifying the interactions of a PDZ domain for 5400 PBM peptides at once. The approach is applicable to any category of protein-binding ligands that can be quantifiable by mass spectrometry.