Biology subjects

Troussicot, L.

Publications and source records attributed to Troussicot, L..

2 recordsLinked to original sources

bioRxiv2025

Metadynamics Simulations for Rational Ligand Design in the Reversible Inhibition of Human Peroxiredoxin 5

Using insights from Funnel Metadynamics, a molecular dynamics protocol that provides a detailed representation of protein-ligand interactions, we investigated how a single heavy-atom modification can enhance the activity of an initial hit against human peroxiredoxin 5. This improvement was validated by NMR experiments and enzyme inhibition assays. Our results illustrate how molecular dynamics simulations offer a rational framework for designing ligands with improved properties starting from low-affinity but selective hits with minimal structural modifications. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/650576v2_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@5e2e4borg.highwire.dtl.DTLVardef@1317896org.highwire.dtl.DTLVardef@e3c283org.highwire.dtl.DTLVardef@f76162_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Disulfide-bond-induced structural frustrationand dynamic disorder in a peroxiredoxin fromMAS NMR

Disulfide bond formation is fundamentally important for protein structure, and constitutes a key mechanism by which cells regulate the intracellular oxidation state. Peroxiredoxins (PRDXs) eliminate reactive oxygen species such as hydrogen peroxide by using a catalytic cycle of Cys oxidation and reduction. High molecular-weight assemblies of PRDXs have recently been shown to additionally act as molecular chaperones. The consequences of disulfide bonds on the dynamics of these large assemblies are poorly understood. We show that formation of disulfide bonds along the catalytic cycle induces extensive s time scale dynamics, as monitored by magic-angle spinning NMR of the 216 kDa-large Tsa1 decameric assembly and solution-NMR of a designed dimeric mutant. We ascribe the conformational dynamics to structural frustration, resulting from conflicts between the disulfide-constrained reduction of mobility and the desire to fulfil other favorable contacts.

biophysics↗