Potential evolutionary advantage of a dissociative search mechanism in DNA mismatch repair

TL;DR

This study compares dissociative and non-dissociative search mechanisms in DNA mismatch repair, finding that dissociative mechanisms are generally advantageous across realistic biological parameters.

Contribution

It provides a semi-analytic and Monte Carlo analysis showing the potential evolutionary advantage of dissociative search mechanisms in DNA repair.

Findings

Dissociative mechanisms are often more efficient in realistic parameter ranges.

Both mechanisms are highly effective for most hemimethylated site distances.

The advantage of dissociative search depends on specific physical parameters.

Abstract

Protein complexes involved in DNA mismatch repair appear to diffuse along dsDNA in order to locate a hemimethylated incision site via a dissociative mechanism. Here, we study the probability that these complexes locate a given target site via a semi-analytic, Monte Carlo calculation that tracks the association and dissociation of the complexes. We compare such probabilities to those obtained using a non-dissociative diffusive scan, and determine that for experimentally observed diffusion constants, search distances, and search durations $\textit{in vitro}$, there is neither a significant advantage nor disadvantage associated with the dissociative mechanism in terms of probability of successful search, and that both search mechanisms are highly efficient for a majority of hemimethylated site distances. Furthermore, we examine the space of physically realistic diffusion constants, hemimethylated site distances, and association lifetimes and determine the regions in which dissociative searching is more or less efficient than non-dissociative searching. We conclude that the dissociative search mechanism is advantageous in the majority of the physically realistic parameter space.