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Towards the Rational Design of RsmE Small-RNA Binders: Insights from Molecular Dynamics Simulations

Created on 24 Oct 2025

Authors

Ormazabal, A., Palma, J. I., Pierdominici-Sottile, G.

Abstract

The RsmZ/RsmE interaction is a key element in post-transcriptional regulation in Pseudomonas species. Experimental studies have shown that alternative fragments of RsmZ, despite displaying only subtle sequence and structural differences, exhibit markedly distinct binding affinities for RsmE. To complicate matters further, the affinities measured for isolated fragments differ substantially from those observed when the same segments are embedded in the full-length sRNA molecule. To explore the origin of these discrepancies, we generated computational models of RsmE dimers bound to one or two sRNA stem loops, including several experimentally studied variants, a couple of truncated forms, and a synthetic construct created by linking two native stem loops with an also native single-stranded region. The unbinding of the RNA fragments from these complexes was studied using Umbrella Sampling simulations, which revealed that base pairs located in the stems, as well as the presence of a linker region, shape the interaction landscape between the protein and RNA, thereby modulating binding affinities. Thus, our findings offer a structural and mechanistic basis for interpreting the experimentally observed differences among RsmZ fragments and establish a conceptual foundation for the future computational design of synthetic sRNAs capable of fine-tuning the RsmZ/RsmE regulatory system in a predictable manner.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 24 Oct 2025.

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