{
  "abstract": "Understanding how conformational dynamics regulate protein complex assembly remains a central challenge in molecular systems biology. Here, we develop a multiscale modeling framework that integrates all-atom molecular dynamics (MD) simulations with rule-based kinetic modeling to investigate the formation of the PP1-GADD34-eIF2 complex, a critical regulator of the integrated stress response. Using umbrella sampling, we compute the potential of mean force (PMF) for key interactions, revealing strong thermodynamic driving forces for eIF2 binding ({Delta}G = -89.5 kJ/mol, KD {approx} 0.07 fM) and moderate affinity for PP1-GADD34 association ({Delta}G = -40.7 kJ/mol, KD {approx} 0.138 M). These energetics inform a PySB-based model that incorporates GADD34's folding state as a continuous variable ({varphi}), linking conformational transitions to holoenzyme assembly and activity. Simulations show that catalytic efficiency is maximized when GADD34 folding free energy is 20 kJ/mol and {varphi} = 0.9, reflecting a highly ordered state stabilized by actin and PP1 binding. Comparative analysis of energy-constrained and optimized parameter regimes reveals that folding-dependent assembly enhances both eIF2 dephosphorylation and information transmission, with channel capacities increasing from <0.002 bits to >5.5 bits. These results demonstrate how conformational regulation encodes system-level function and underscore the utility of multiscale models in bridging molecular energetics with dynamic biochemical control.",
  "abstract_shown": true,
  "affiliations": [
    "Altos Labs Inc"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "F. Fontana"
    },
    {
      "name": "B. Bogin"
    },
    {
      "name": "M. Irvin"
    },
    {
      "name": "M. Ozen"
    },
    {
      "name": "Z. A. Levine"
    },
    {
      "affs": [
        0
      ],
      "name": "C. F. Lopez"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cte2s5nrspbx3.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.23.753607",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753607v1.full",
  "id": "cte2s5nrspbx3",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753607v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7214244982",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753607v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-23",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cte2s5nrspbx3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:18Z",
      "native_id": "10.64898/2026.09.23.753607",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753607v2"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Folding-Driven Control of the Functional PP1 Complex via Multiscale Modeling",
  "title_text": "Folding-Driven Control of the Functional PP1 Complex via Multiscale Modeling",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:58Z",
  "url": "https://research.draconitic.com/paper/cte2s5nrspbx3",
  "venue": "bioRxiv",
  "versions": []
}