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Peer-reviewedCC BY 4.0Catalysts

Beyond Geometric Pre-Reaction States: A Bottleneck-Guided Framework for PET Hydrolase Engineering

  • Xinglin Zhang1
  • Wei Miao2
  • Jiayi Li3
  1. 1YK Pao School, 1800 Lane 900 North Sanxin Road, Songjiang District, Shanghai 201620, China
  2. 2McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA
  3. 3Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
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Abstract

Enzymatic depolymerization of poly(ethylene terephthalate) (PET) is a promising route toward closed-loop plastic recycling, yet the catalytic factors that become limiting once an enzyme already samples reaction-ready geometries remain unclear. Here, we compare two parent-variant pairs, FAST-PETase/FAST-Y61Q and LCC-ICCG/LCC-A2 (H218Y/N248D), using replicated molecular dynamics (MD) simulations, pre-reaction-state (PRS) analysis, noncovalent-interaction characterization, quantum-mechanical cluster calculations, and distortion/interaction activation-strain (DIAS) analysis. Y61Q remodels the second-shell environment and the conformational ensemble of the PET ethylene-glycol linker, thereby increasing the population of Bürgi–Dunitz compatible attack geometries. By contrast, LCC-A2 and LCC-ICCG exhibit similar populations of the two-coordinate geometric PRS, whereas LCC-A2 shows more favorable oxyanion-hole organization, Ser-His proton-transfer readiness, substrate polarization, and transition-state interactions, together with a lower calculated acylation barrier. These results support a bottleneck-guided view of PET-hydrolase engineering: when reaction-ready geometries are sparsely populated, mutations can act primarily by improving geometric preorganization; once such geometries are already abundant, further gains can arise from improving the chemical quality of the PRS ensemble. This framework distinguishes PRS quantity from PRS quality and provides a mechanistic basis for selecting stage-appropriate descriptors in PET-hydrolase design.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026beyond,
  title = {{Beyond Geometric Pre-Reaction States: A Bottleneck-Guided Framework for PET Hydrolase Engineering}},
  author = {Xinglin Zhang and Wei Miao and Jiayi Li},
  journal = {Catalysts},
  year = {2026},
  month = oct,
  doi = {10.3390/catal16100906},
  url = {https://www.mdpi.com/2073-4344/16/10/906},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Beyond Geometric Pre-Reaction States: A Bottleneck-Guided Framework for PET Hydrolase Engineering
AU  - Xinglin Zhang
AU  - Wei Miao
AU  - Jiayi Li
PY  - 2026
DA  - 2026/10/13
JO  - Catalysts
DO  - 10.3390/catal16100906
UR  - https://www.mdpi.com/2073-4344/16/10/906
AB  - Enzymatic depolymerization of poly(ethylene terephthalate) (PET) is a promising route toward closed-loop plastic recycling, yet the catalytic factors that become limiting once an enzyme already samples reaction-ready geometries remain unclear. Here, we compare two parent-variant pairs, FAST-PETase/FAST-Y61Q and LCC-ICCG/LCC-A2 (H218Y/N248D), using replicated molecular dynamics (MD) simulations, pre-reaction-state (PRS) analysis, noncovalent-interaction characterization, quantum-mechanical cluster calculations, and distortion/interaction activation-strain (DIAS) analysis. Y61Q remodels the second-shell environment and the conformational ensemble of the PET ethylene-glycol linker, thereby increasing the population of Bürgi–Dunitz compatible attack geometries. By contrast, LCC-A2 and LCC-ICCG exhibit similar populations of the two-coordinate geometric PRS, whereas LCC-A2 shows more favorable oxyanion-hole organization, Ser-His proton-transfer readiness, substrate polarization, and transition-state interactions, together with a lower calculated acylation barrier. These results support a bottleneck-guided view of PET-hydrolase engineering: when reaction-ready geometries are sparsely populated, mutations can act primarily by improving geometric preorganization; once such geometries are already abundant, further gains can arise from improving the chemical quality of the PRS ensemble. This framework distinguishes PRS quantity from PRS quality and provides a mechanistic basis for selecting stage-appropriate descriptors in PET-hydrolase design.
SN  - 2073-4344
ER  -