Transcription factors (TF) are proteins that bind to a target site on chromatin and orchestrate transcription. We try to model the interphase chromatin as a network where each bead of the simulated polymer acts as a node and the TF as an unbiased random walker, hopping to other nodes in the neighborhood. From existing literature on the network, it is known that the mean first passage time (MFPT) of a random walker between any two nodes on a general network follows a set of particular scaling laws.
Lamins are principal nucleoskeletal proteins of all mammalian cells, which impart rigidity to nuclear morphology and ensure the resilience of the nucleus by forming filamentous meshwork under the inner nuclear membrane, called nuclear lamina. Over the recent years, mutations in lamins have been found to cause a cluster of human diseases, collectively termed laminopathies (e.g., dilated cardiomyopathy (DCM), Hutchinson–Gilford progeria syndrome etc.). One of the significant features of such mutations is the abrupt disappearance of the nuclear lamina and the formation of multiple lamin aggregates in the nucleoplasm. In this study, we perform coarse-grained simulations (using LAMMPS) of a small region near the membrane of the nucleus to investigate the role of interactions between different nuclear components (chromatin, lamin and nuclear membrane) in WT cells and possible changes in those interactions which can lead to a mutant configurations.
Coarse-grained chromatin models are essential to interpret various experimental observations and predicting physical principles behind chromatin organization. Most existing polymer models consider chromatin as an array of beads connected by springs. Each bead represents chromatin segments of genomic length 1 kbp to 1 Mbp (depending on the context). Models also assume various polymer properties as input, such as the spring constant of the connecting spring between beads, bending rigidity, coarse-grained bead sizes, equilibrium bond lengths between neighboring beads, equilibrium angles between three consecutive beads etc. In a recent study, using extensive simulations, we have predicted these quantities essential for the polymer representation of chromatin.