{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "YK Pao School, 1800 Lane 900 North Sanxin Road, Songjiang District, Shanghai 201620, China",
    "McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA",
    "Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xinglin Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Wei Miao"
    },
    {
      "affs": [
        2
      ],
      "name": "Jiayi Li",
      "orcid": "0009-0000-8417-7660"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d8a2jax5rq6ev.bib",
  "cited_by": 0,
  "doi": "10.3390/catal16100906",
  "fulltext_url": null,
  "id": "d8a2jax5rq6ev",
  "issns": [
    "2073-4344"
  ],
  "landing_url": "https://www.mdpi.com/2073-4344/16/10/906",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Chemical Reaction Mechanisms"
    ]
  ],
  "openalex": "W7221697697",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-13",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/d8a2jax5rq6ev.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:43Z",
      "native_id": "10.3390/catal16100906",
      "source": "crossref",
      "url": "https://www.mdpi.com/2073-4344/16/10/906"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Chemical Reaction Mechanisms",
      "subfield": "organic"
    }
  ],
  "title": "Beyond Geometric Pre-Reaction States: A Bottleneck-Guided Framework for PET Hydrolase Engineering",
  "title_text": "Beyond Geometric Pre-Reaction States: A Bottleneck-Guided Framework for PET Hydrolase Engineering",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:43Z",
  "url": "https://research.draconitic.com/paper/d8a2jax5rq6ev",
  "venue": "Catalysts",
  "versions": []
}