From covalent transition states in chemistry to noncovalent in biology: from to value analysis of protein folding.

Solving the mechanism of a chemical reaction requires determining the structures of all the ground states on the pathway and the elusive transition states linking them. 2024 is the centenary of Brønsted's landmark paper that introduced the -value and structure-activity studies as the only experimental means to infer the structures of transition states. It involves making systematic small changes in the covalent structure of the reactants and analysing changes in activation and equilibrium-free energies.

NF-κB Rel subunit exchange on a physiological timescale.

The Rel proteins of the NF-κB complex comprise one of the most investigated transcription factor families, forming a variety of hetero- or homodimers. Nevertheless, very little is known about the fundamental kinetics of NF-κB complex assembly, or the inter-conversion potential of dimerised Rel subunits. Here, we examined an unexplored aspect of NF-κB dynamics, focusing on the dissociation and reassociation of the canonical p50 and p65 Rel subunits and their ability to form new hetero- or homodimers.

AlphaFold - A Personal Perspective on the Impact of Machine Learning.

I outline how over my career as a protein scientist Machine Learning has impacted my area of science and one of my pastimes, chess, where there are some interesting parallels. In 1968, modelling of three-dimensional structures was initiated based on a known structure as a template, the problem of the pathway of protein folding was posed and bets were taken in the emerging field of Machine Learning on whether computers could outplay humans at chess. Half a century later, Machine Learning has progressed from using computational power combined with human knowledge in solving problems to playing chess without human knowledge being used, where it has produced novel strategies.

Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm.

We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of the p53 mutome, we have now analyzed the effects of other cancer-associated mutations at codon 220 on the structure, stability, and dynamics of the p53 DNA-binding domain (DBD). We found that the oncogenic Y220H, Y220N, and Y220S mutations are also highly destabilizing, suggesting that they are largely unfolded under physiological conditions.

ChemBioChem@20-Some Reflections.

Looking back, looking forward: In 2000, ChemBioChem debuted. The chemistry of carbohydrates, nucleic acids, peptides, proteins, natural products and other small molecules had reached a level that allowed biological questions to be probed. Today, there is no end in sight to studying biological matter with chemical tools or making use of biological methods to produce chemicals.