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Theoretical Framework for Calculating Sequence-Dependent Physical Properties of Nucleosomes

Enrico Skoruppa1,2,*,†, Manish Yadav2,*, Thor van Heesch3, Jocelyne Vreede3, and Helmut Schiessel2,4

  • 1School of Physics and Astronomy, University of Edinburgh, Peter Guthrie Tait Road, Edinburgh EH9 3FD, United Kingdom
  • 2Cluster of Excellence Physics of Life, TU Dresden, Arnoldstraße 18, 01307 Dresden, Germany
  • 3Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
  • 4Institut für Theoretische Physik, TU Dresden, 01062 Dresden, Germany

  • *These authors contributed equally to this work.
  • †Contact author: esk.phys@gmail.com
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PRX Life 4, 023017 – Published 21 May, 2026

DOI: https://doi.org/10.1103/rh7r-ysrf

Abstract

The positioning of nucleosomes, the most abundant nucleoprotein complex in eukaryotes, and their physical properties are strongly influenced by sequence-dependent geometric and elastic properties of the wrapped DNA. At present, the theoretical study of this system is largely limited to numerical computation, and access to entropic contributions has been challenging. In particular, the toolset for the systematic introduction of binding-site-mediated constraints that retains analytical tractability—beyond uniform superhelical wrapping—is currently lacking. Here, we present a mathematical framework for introducing such constraints in the context of the rigid-base-pair model that permits local DNA relaxation and yields closed-form expressions for elastic binding free energies. Importantly, the methodology enables the evaluation of individual contributions to the free energy, including entropy. Benchmarking against numerical solutions obtained via Monte Carlo sampling and validation with experimental data ranging from competitive nucleosome reconstitution to spontaneous nucleosome breathing and force-induced unwrapping demonstrates quantitative fidelity. The approach enables genome-wide evaluation of nucleosome binding affinities and can be readily extended to noncanonical and epigenetically modified DNA or histone cores. While the present study is based on the rigid-base-pair model, the same ideas extend to any rigid-body-based model, opening a route to a broad class of problems in biomolecular modeling.

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PRX Life 4, 023017– Published 21 May, 2026
  • Received 14 November 2025
  • Accepted 20 April 2026
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