A polymer physics model of the interphase cell nucleus for radiobiological simulations

Advances in chromatin architectures achieved through super-resolution imaging and high-throughput chromosome conformation capture (Hi-C) techniques remain to be integrated into the modeling framework of radiobiology. In this study, the chromosomal and chromatin interactions in an interphase cell nucleus were described by polymer physics principles. To overcome the prohibitive computational cost, a multi-stage relaxation strategy was employed to decouple the relaxation processes of different structural levels. A distance-dependent DNA end rejoining model and a graph theory-based connected component analysis algorithm were implemented to simulate chromosome aberrations. Experimental measurements of chromosome aberrations in human skin fibroblasts exposed to both γ-rays and α particles were selected to benchmark the performance. The model efficiently reproduced 3D chromatin architectures, including chromosome territories and subcompartments, chromatin domains and loops. The predicted contact map and contact probability were consistent with Hi-C measurements. Model predicted dicentrics, interstitial deletions, and total aberrations aligned with experimental data within 20% for γ-rays and α particles, showing substantial improvement over previous reports. The proposed polymer physics-based model bridges structural biology and radiobiological simulations, demonstrating strong potential for accurate prediction of DNA damage and chromosome aberrations. Future refinements will integrate spatio-temporal repair dynamics and whole-genome sequencing data to enhance high-LET radiobiological effect predictions.