{
  "id": 3181303,
  "title": "Enhanced-Sampling Molecular Dynamics Recovers Rare Functional RNA Conformations Across Diverse Structural Contexts",
  "url": "https://urgent.news/2026/08/24/enhanced-sampling-molecular-dynamics-recovers-rare-functional-rna",
  "topic": "science",
  "section": "Science",
  "published": "2026-08-24T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.22.746453v1?rss=1"
  },
  "original_language": "en",
  "account": "Determining the conformational ensembles of RNA molecules is crucial for understanding their function and improving RNA-targeted drug discovery. However, low-populated alternative states are challenging to resolve at an atomic level. The starting library for experimental refinement often contains conformations already present, making library generation the limiting factor. To address this issue, researchers compared conventional molecular dynamics (cMD) with several enhanced sampling methods, including Gaussian-accelerated MD (GaMD), replica-exchange Gaussian-accelerated MD (Rex-GaMD), replica-exchange with solute tempering (REST2), temperature replica-exchange MD (T-REMD), structure-prediction based methods FARFAR2 and AlphaFold 3. Upon refinement, T-REMD demonstrated the most accurate ensemble through both experimental residual dipolar couplings (RDC) and ensemble-averaged QM/MM chemical shifts. Its advantage was linked to a broader and more continuous coverage of the interhelical conformational landscape. T-REMD with a broad temperature-range also effectively sampled conformations resembling excited state 1 (ES1) and the U23-A27-U38 base-triple, without the need for these states to be specified during library generation. Enhanced ensembles led to improved coverage of experimentally observed ligand-bound TAR conformations and better ensemble-based virtual screening, highlighting the relationship between structural accuracy and functional utility. Applying the same workflow to the preQ1 class I riboswitch and the UUCG tetraloop further improved agreement with experimental data. The findings establish replica-exchange enhanced sampling, particularly T-REMD, as an effective approach for constructing experimentally validated RNA ensembles and accessing conformations corresponding to rare functional substates.",
  "summary": "Accurate determination of RNA conformational ensembles is essential for understanding RNA function and advancing RNA-targeted drug discovery, yet lowly-populated alternative states remain difficult to resolve with atomistic detail. A central constraint is that experimental refinement can only select conformations already present in the starting library, making library generation the limiting…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}