What question did this study set out to answer?

To characterize the structure and dynamics of the i-motif formed by the HRAS gene promoter using all-atom simulations and biophysical assays.

March 7, 2026

Combined All-Atom Simulations and Biophysical Assays Uncover Loop-Driven Stabilization in the HRAS i-motif

Puntos clave

To characterize the structure and dynamics of the i-motif formed by the HRAS gene promoter using all-atom simulations and biophysical assays.
Conducted all-atom simulations to explore iHRAS dynamics.
Performed biophysical experiments to validate simulation findings.
Analyzed loop dynamics and ion binding effects on structural stability.
iHRAS exhibits multiple interconverting conformational states.
A protective G:G cap stabilizes the core i-motif structure.
Structural variability is most significant in loops due to K+ ion binding.

Resumen

I-motifs are noncanonical DNA secondary structures stabilized by hemiprotonated C+:C base pairs. Their intrinsic flexibility, conformational heterogeneity, and sensitivity to environmental conditions often hinder structural characterization. Here, all-atom simulations, combined with biophysical experiments, were used to characterize the structure of the i-motif monomer formed by the HRAS gene promoter (iHRAS), a member of the RAS proto-oncogene family. Our results reveal that iHRAS exhibits intricate conformational behavior characterized by multiple interconverting states. The core i-motif is stabilized by a protective G:G cap, a recurrent i-motif-stabilizing factor, on one side, while the C+:C base pairs content on the other side is variable. Structural heterogeneity is most pronounced in loops, which sample several base-exposed states aided by K+ ion binding. These findings contribute to a deeper understanding of the i-motif structure and dynamics.

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