Bullied no more : When DNA shoves proteins around(Knots and soft-matter physics: Topology of polymers and related topics in physics, mathematics and biology)

Abstract

Most studies of protein-DNA interactions take a protein-centric perspective-giant proteins "bully" a static DNA polymer into a recognizable configuration. The structure of the protein is considered the primary determinant in the interaction, and DNA is considered, by comparison, merely a passive substrate. There are likely several reasons for this view, but the most important reason, perhaps, is that static crystal structures, which are the most vivid and compelling pictures we have, contain only a short fragment of DNA. The mechanistic explanations for protein-DNA recognition, therefore, usually arise from the structure of the protein. But protein structure does not tell the whole story. We propose that to understand protein-DNA interactions, a more holistic perspective must be taken. Protein-DNA interactions involve not just the protein, but also what we now know are incredibly dynamic DNA molecules, and the equally dynamic solvent molecules and counterions that surround them. Here we consider the ways that DNA topology can affect protein-DNA interactions, and focus, in particular, on the local, sequence-specific properties of DNA that do not occur when DNA is in the relaxed B-form as it is found in nearly all DNA crystal structures and is employed in the overwhelming majority of biophysical and biochemical studies of DNA structure and protein-DNA binding. DNA in cells is not inert like the linear B-form used in such experiments and it does not have naked ends. Instead, DNA in cells has topology, and topology affects: curvature, twist, kinking, base flipping, denaturation, and counterion concentrations, in addition to the likelihood that two DNA helices come together to form DNA juxtapositions.