Thermal Adaptation in β-Glucosidases Reshapes a Conserved Dynamic Coupling Sector

How protein sequences preserve functional conformational dynamics under thermal stress is a long-standing question in molecular evolution. Thermophilic enzymes are often assumed to gain heat tolerance mainly through enhanced structural rigidity, but a new comparative study of three glycoside hydrolase family 1 (GH1) β-glucosidases suggests a more nuanced picture: enzymes sharing the same fold can achieve thermal adaptation through distinct organizations of correlated motion, with a conserved dynamic sector emerging as a shared focal point.

The study, published in PLOS Computational Biology, compared three β-glucosidases—BsBgl1A, 9UPT, and LQBG8—that share a conserved (β/α)8 TIM-barrel fold yet display optimal temperatures of approximately 45, 65, and 70 °C, respectively. The authors, led by Li-Ting Zheng and colleagues, integrated comparative structural analysis, three independent 1 microsecond molecular dynamics simulations at 300, 325, and 350 K, neural relational inference of residue-level dynamic coupling, and family-level coevolutionary analysis to link thermal phenotype with dynamic organization.

Across all simulated temperatures, the three enzymes retained their global compactness and principal secondary-structure framework, indicating that differences in structural deviation and residue flexibility did not reflect large-scale unfolding. BsBgl1A, the least thermally adapted enzyme, showed the strongest temperature sensitivity, with increased structural deviation and residue mobility at 350 K. Its inferred interaction network responded non-monotonically to temperature, exhibiting pronounced overcoupling at 325 K followed by reduced connectivity at 350 K.

The two more thermally adapted enzymes behaved differently. 9UPT maintained relatively restrained residue dynamics and a highly reproducible coupling topology across temperatures. LQBG8 combined substantial local conformational flexibility with persistent long-range coupling and retained the highest directed network density at 350 K. Rather than simply stiffening their structures, the more thermotolerant enzymes preserved or reorganized their networks of correlated residue motion under elevated temperature.

A striking convergence emerged across the three enzymes: the βα5–βα7 region repeatedly appeared as a shared structural and dynamic center. Coevolutionary couplings inferred from family-level analysis were also enriched in TIM-barrel-associated regions that spatially converged on this same sector. The correspondence between dynamic coupling and coevolutionary enrichment suggests long-term evolutionary constraint on this structural region, although the authors caution that it does not establish direct selection on the network as an independent functional unit.

The findings indicate that thermal adaptation in GH1 β-glucosidases is not adequately explained by uniform structural rigidification. Instead, greater thermal adaptation appears associated with the persistence or reorganization of a βα5–βα7-centered dynamic coupling pattern under elevated temperature, while enzymes with the same conserved fold may adopt distinct dynamic strategies. The authors present this as a testable framework in which thermostability reflects a balance among local stabilization, regional flexibility, and the resilience of higher-order dynamic organization.

Subject of Research: How thermally adapted GH1 β-glucosidases maintain functional conformational dynamics through a conserved coupling sector.

Article Title: Evolutionary and dynamic constraints converge on a conserved coupling sector in thermally adapted GH1 β-glucosidases

Article References: Zheng, L.-T., Li, Y., He, X., Yang, L.-T., Zhao, D.-R., Liu, M.-T., Sang, P., & Yang, L.-Q. (2026). Evolutionary and dynamic constraints converge on a conserved coupling sector in thermally adapted GH1 β-glucosidases. PLOS Computational Biology, 22(10), e1014879. https://doi.org/10.1371/journal.pcbi.1014879

Image Credits: AI Generated

DOI: 10.1371/journal.pcbi.1014879

Keywords: GH1 β-glucosidases, thermal adaptation, molecular dynamics, TIM-barrel, protein dynamics, coevolution, neural relational inference, thermostability, βα5–βα7 region, conformational dynamics, Evolutionary, dynamic