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PreprintCC BYbioRxiv

Gene-family-dependent thermodynamic effects of oncogenic mutations on nucleosome-DNA binding stability: a comparative molecular dynamics study across 22 cancer hotspots

  • S. Freudenberger
  • E. Boczko
  • S. Goel
  • R. Maitra1
  1. 1Yeshiva University Yeshiva College
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Abstract

Oncogenic mutations are known to occur at non-random rates and specific hotspots, yet the structural and thermodynamic factors underlying these hotspots remain poorly understood. This study presents molecular dynamics simulations of 22 cancer hotspots across 10 oncogene families, simulated as histone-DNA complexes. Across 18 of 22 mutations, thermodynamic effects were predominantly localized to within 6 [A] of the DNA-histone interface (mean capture 104%), with van der Waals interactions driving the effect at the thermodynamic extremes, indicating that oncogenic mutations alter nucleosome binding through precise local contact changes rather than global structural rearrangements. Further, analysis revealed a gene-family correlated pattern in thermodynamic stability. RAS family mutations showed a consistent trend toward nucleosome stabilization (mean {Delta}{Delta}G = -4.82 kcal mol-1), while kinase domain mutations trended toward destabilization (mean {Delta}{Delta}G = +40.12 kcal mol-1), a difference reaching statistical significance in this exploratory analysis (Mann-Whitney U, p = 0.008). This interface-specific mechanism, combined with the gene-family-correlated thermodynamic pattern, provides a biophysical framework for understanding nucleosome-level contributions to cancer hotspot mutation biology.

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Cite

BibTeXRIS
BibTeX
@misc{freudenberger2026genefamilydependent,
  title = {{Gene-family-dependent thermodynamic effects of oncogenic mutations on nucleosome-DNA binding stability: a comparative molecular dynamics study across 22 cancer hotspots}},
  author = {S. Freudenberger and E. Boczko and S. Goel and R. Maitra},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.28.754892},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.28.754892v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Gene-family-dependent thermodynamic effects of oncogenic mutations on nucleosome-DNA binding stability: a comparative molecular dynamics study across 22 cancer hotspots
AU  - S. Freudenberger
AU  - E. Boczko
AU  - S. Goel
AU  - R. Maitra
PY  - 2026
DA  - 2026/09/28
PB  - bioRxiv
DO  - 10.64898/2026.09.28.754892
UR  - https://www.biorxiv.org/content/10.64898/2026.09.28.754892v1
AB  - Oncogenic mutations are known to occur at non-random rates and specific hotspots, yet the structural and thermodynamic factors underlying these hotspots remain poorly understood. This study presents molecular dynamics simulations of 22 cancer hotspots across 10 oncogene families, simulated as histone-DNA complexes. Across 18 of 22 mutations, thermodynamic effects were predominantly localized to within 6 [A] of the DNA-histone interface (mean capture 104%), with van der Waals interactions driving the effect at the thermodynamic extremes, indicating that oncogenic mutations alter nucleosome binding through precise local contact changes rather than global structural rearrangements. Further, analysis revealed a gene-family correlated pattern in thermodynamic stability. RAS family mutations showed a consistent trend toward nucleosome stabilization (mean {Delta}{Delta}G = -4.82 kcal mol-1), while kinase domain mutations trended toward destabilization (mean {Delta}{Delta}G = +40.12 kcal mol-1), a difference reaching statistical significance in this exploratory analysis (Mann-Whitney U, p = 0.008). This interface-specific mechanism, combined with the gene-family-correlated thermodynamic pattern, provides a biophysical framework for understanding nucleosome-level contributions to cancer hotspot mutation biology.
ER  -