Recognition in Confinement: The Dynamics of Homologous Gene Pairing

How can protein-independent, side-by-side alignment of homologous double-stranded DNA (ds-DNA) 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, favouring homologous over non-homologous alignment. However, HCT has largely been developed for straight, rigid dsDNA rods, an approximation limited to roughly one persistence length ({ell}B {approx} 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, in order to come closer to understanding how homologous genes pair in vivo. We simulate two homologous chains within spherical cavities of radii 0.3-1 times their free-space gyration radius under two limiting ionic conditions. We found that confinement warrants homologous pairing; it occurs on microsecond timescales and depends non-monotonically on confinement size, with an optimal confinement that accelerates pairing while avoiding tangled states and metastable trapping in an ion-dependent manner. To resolve pairing dynamics, we develop a kinetic theory and fit it to simulation trajectories, distinguishing rates of independent pairing modes underlying bubble formation and fraying. Together, these results support a physical mechanism for homologous pairing beyond the rigid-rod limit and suggest how confinement can promote both encounter and stabilisation within the HCT framework.