{
  "abstract": "The present in silico study provided the adaptive binding of seven physiologically active molecules, including four non-peptide hormones (cortisol, estradiol, triiodothyronine, melatonin) and three vitamins (methyltetrahydrofolate, pyridoxal phosphate, thiamine), alongside argireline as a benchmark, at hotspot-enriched interfaces of full C2AB-domain of Synaptotagmin 1 (Syt1), using molecular docking study and molecular dynamics (MD) simulations. Linear correlations of MD-features and nonlinear KPCA-IG-based ranking of features and ligands yielded deeper mechanistic insights. All ligands exhibited spontaneous binding with strong negative {Delta}Gbinding values. Fifteen hotspots, clustered across the C2A, C2B, and C2AB-interlink regions, were dominated by hydrophobic and van der Waals interactions. Several hotspots and non-hotspots corresponded to Syt1 residues that are reported to link with Ca2+-dependent phenomena and membrane vesicular fusion. Solvent-excluded volume (VSE) analyses showed that local hotspot burial and global desolvation together influenced protein adaptability, distinguishing ligands with similar hotspots but divergent thermodynamics. Linear correlations established {Delta}Gbinding as an indicator of hydrophobic hotspot burial. KPCA-IG identified {Delta}VSE and RMSD as dominant mechanistic features capturing cooperative induced-fit responses. Pyridoxal phosphate, melatonin and triiodothyronine emerged as mechanistically top adaptive binders, involving adjustable desolvation, hotspot expansion, optimal flexibility and pose retention. Methyltetrahydrofolate and cortisol showed intermediate burial-dominated cooperativity. Argireline, thiamine and estradiol exhibited ligand-specific burial-dominated, pose-locked and adaptability-limited bindings. Overall, our study demonstrates that desolvation control, induced-fit adaptability and structural flexibility, not {Delta}Gbinding alone, govern Syt1-ligand binding, revealing Syt1 as a versatile presynaptic target for modulation by these bioactive molecules.",
  "abstract_shown": true,
  "affiliations": [
    "University of Calcutta"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "name": "S. Hazra"
    },
    {
      "name": "B. K. Tiwary"
    },
    {
      "name": "A. Ghosh Chaudhuri"
    },
    {
      "affs": [
        0
      ],
      "name": "N. Chakrabarti"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9mt7bfbvf9y2k.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.18.760018",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.18.760018v1.full",
  "id": "9mt7bfbvf9y2k",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.18.760018v1",
  "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",
      "bioinformatics"
    ],
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7223045782",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.18.760018v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-18",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9mt7bfbvf9y2k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:41Z",
      "native_id": "10.64898/2026.10.18.760018",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.18.760018v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "Mechanistic Insights into Adaptive Binding of Vitamins and Hormones at Hotspot-Enriched Interfaces of the Synaptotagmin 1 C2AB Domain",
  "title_text": "Mechanistic Insights into Adaptive Binding of Vitamins and Hormones at Hotspot-Enriched Interfaces of the Synaptotagmin 1 C2AB Domain",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:41Z",
  "url": "https://research.draconitic.com/paper/9mt7bfbvf9y2k",
  "venue": "bioRxiv",
  "versions": []
}