Markov Modeling of Protein Diffusion on Telomeric DNA

Abstract

Telomeres, the termini of linear chromosomes, solve two major issues of genome maintenance in Eukaryota: hide the loose ends of DNA from the DNA repair machinery, and fix the end-replication problem by allowing for repeated shortening and extension of the tandem repeating fragments. The protective nucleoprotein complex is not static, though, with e.g. cell-cycle dependent opening and closing of the telomeric loop necessary for DNA replication. Due to the repetitive nature of the telomeric sequence, all telomeric DNA-binding proteins also constantly slide along the DNA, moving between adjacent binding sites. In particular, the sliding of POT1 along single-stranded DNA prevents the unwanted formation of G-quadruplexes on the 3′-terminal overhang, while TRF1 and TRF2 slide along the double-stranded portion to assemble the shelterin. Here, we use molecular simulations augmented with Markov models and free energy methods to model the diffusion of TRF1 and POT1 along both telomeric and polyA DNA in atomistic resolution. Instead of a simple geometrical, center-of-mass position based approach, we use intermolecular contacts as a more informative descriptor of diffusive processes, particularly when subdiffusion comes into play. Comparison with experimental data allows to probe the sensitivity of the model to its parameters. With this approach, we outline a general methodology for the atomistic modelling of sliding-like diffusion along biopolymers, a crucial stage in the dynamic formation of sequence-specific complexes.