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Recognition in Confinement: The Dynamics of Homologous Gene Pairing

Ehud Haimov1,2, Jonathan G. Hedley3, Natalia E. Simonowicz1, Yaxuan Xiao1, Andrew Stannard1, Gleb Oshanin4, Angelo Rosa5, Yuval Elani6, and Alexei A. Kornyshev1,*

  • *Contact author: a.kornyshev@imperial.ac.uk
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PRX Life 4, 033023 – Published 2 September, 2026

DOI: https://doi.org/10.1103/n5cv-svz2

Abstract

How can protein-independent, side-by-side alignment of homologous double-stranded DNA (dsDNA) arise as an early step in genome repair and genetic exchange, and what determines their kinetics under confinement? Although recombination proteins are known to facilitate this process, experiments indicate that an initial side-by-side arrangement of homologs can occur even in their absence. Helical Coherence Theory (HCT) proposes that sequence-dependent distortions of the double helix lead to commensurate charge patterns between interacting dsDNAs, favoring homologous over nonhomologous alignment. However, HCT has largely been developed for straight, rigid dsDNA rods, an approximation limited to roughly one persistence length (ℓB≈50 nm), leaving the question open as to how recognition manifests in longer, fluctuating chains. Moreover, the dynamics and timescales of homolog searching under confinement, and the internal dynamics of the paired state, such as transient formation of local unpaired regions (“bubbles”) and end fraying, remain unexplored. Here we extend HCT to dsDNA chains of multiple persistence lengths under confinement using coarse-grained simulations with a custom HCT-based force field to promote our understanding of how homologous genes pair in vivo. We simulate two homologous chains in spherical cavities spanning 0.3 to 1 times the free-space gyration radius under two limiting ionic conditions, and use the ratio of confinement radius to free-space gyration radius as a control parameter. Pairing occurs on microsecond timescales, with intermediate confinement giving the most favorable balance between rapid encounter and avoidance of kinetically trapped states. This behavior reflects a crossover from diffusion-limited search under weak confinement to trapping-dominated dynamics under strong confinement. To resolve pairing dynamics, we develop and fit a kinetic theory to simulation trajectories, distinguishing rates of independent pairing modes underlying bubble formation and fraying. Together, these results establish a general physical principle: confinement acts as a control parameter that governs a crossover between diffusion-limited and kinetically trapped pairing regimes for homologous DNA chains, contributing to a minimal protein-free mechanism for homologous recognition on biologically relevant timescales.

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PRX Life 4, 033023– Published 2 September, 2026
  • Received 5 August 2025
  • Accepted 14 July 2026
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Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

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