A stochastic hybrid model for DNA replication incorporating protein mobility dynamics

DNA replication is a complex process that ensures the maintenance of genetic information. Recently, advancements in chromatin conformation capture techniques have enabled the modeling of DNA replication as a spatio-temporal process. Here, we present a stochastic hybrid model for DNA replication that incorporates protein mobility dynamics and 3D chromatin structure. Performing simulations for three model variations and a broad range of parameter values, we collected about 300,000 in silico replication profiles for fission yeast and conducted a parameter sensitivity analysis. We find that the number of firing factors initiating replication is rate-limiting and dominates the time until completion of DNA replication. In support of recent work, we also find that explicitly modeling the recruitment of firing factors by the spindle pole body (SPB) best reca-pitulates published origin efficiencies, and independently validate these findings in vivo . Accounting for probabilistic effects in molecular interactions, we further investigated the replication kinetics inherent to the model and were able to capture known properties of DNA replication. Importantly, we confirm earlier observations that, without further assumptions, the characteristic shape of a function commonly used to describe replication kinetics arises from a rate-limiting number of firing factors in conjunction with their recycling upon replication fork collision. While the model faithfully recapitulates global spatial patterns of replication initiation, additional analysis of spatial concurrence and competition suggests that a uniform binding probability is too simplistic to capture local neighborhood effects in origin firing. In summary, our model provides a framework to realistically simulate DNA replication for a complete eukaryotic genome, and to investigate the relationship between three-dimensional chromatin conformation and DNA replication timing.