Thermal resilience of the archaeal heat shock Protein-14 (sHSP14) dimer: Insights into Nature's molecular design.

Thermo-physical perturbation is expected to weaken protein stability and assembly. Yet, in the biological context, chaperones such as heat shock proteins (HSPs) must counter perturbative effects to preserve proteostasis. Herein, we report that the sHSP14, a small heat shock protein from the extremophile Sulfolobus, inverts this paradigm through thermal reinforcement. Fully atomistic in silico sampling is exploited to reveal that elevated temperatures enhance dimeric stability via enthalpic consolidation that persists even at high salinity. This archaeal chaperone operating with minimal molecular machinery achieves robustness through elegant design: β-strand swapping creates topological architecture, while a strategic charged residue network (Arg17, Asp28, Arg66, Asp41, Arg79, Lys74) and nearly 40 preserved hydrogen bonds maintain stabilization even upon temperature elevation. These findings redefine our understanding of extremophile adaptation and offer blueprints for engineering next-generation thermostable biomolecules.