Chapter 3: Opposites Attract: Shape and Electrostatic Complementarity in Protein-DNA Complexes

Proteins and DNA form complexes due to complementary properties of their molecular structure and electrostatic potential at the binding interface. While proteins predominantly consist of globular domains complemented by linkers and tails, DNA generally forms a double helix through hydrogen bonding between bases on opposite strands. Globular domains of DNA-binding proteins are condensed structures with little flexibility that often bind the major groove while protein linkers and tails are extremely flexible, which play a role for many protein families in binding the minor groove. Protein residues have been observed to recognize the sequence-dependent shape of DNA, engage in hydrogen bonding with the functional groups of the bases, form water-mediated hydrogen bonds, or be attracted by the negative electrostatic potential that surrounds DNA. Due to the polyanionic character of the double helix, basic side chains, such as arginines and lysines, are key protein residues involved in DNA binding. Much structural and biophysical knowledge on protein-DNA recognition has been gathered from experimental and computational studies, but the vast amount of DNA sequence information from genomic studies demonstrates that our understanding of the molecular origins of protein-DNA binding specificity, gene regulation, and chromatin organization is far from completion. The present book chapter offers a new perspective on protein-DNA binding, which emphasizes the need to consider shape and electrostatic complementarity together when rationalizing protein-DNA complex formation.