Abstract
This chapter focuses on how different phenomena influence the regulation of gene expression and offer chemical and structural explanations of gene regulation. This chapter also discusses how to construct artificial transcription factors having novel specificity and functions.•B-DNA, the dominant conformation of genomic DNA, contains sequence-dependent conformational heterogeneity. We have discussed in detail how this heterogeneity is reflected in many structural parameters of individual base pairs.•DNA and protein are both polyelectrolytes. Counterions and water molecules surround both DNA and proteins in solution. A fraction of the water of hydration is tightly associated with macromolecules. DNA-protein interactions are broadly classified into two groups: sequence-specific interactions and nonsequence-specific interactions. Interaction between a protein and the DNA leads to the release of counterions and water to the bulk solvent. The release of water and ions is entropically favorable and a significant component of the binding free energy.•Sequence-specific and nonsequence-specific DNA-protein complexes differ in their structures. Structure elucidation of the sequence-specific complex and the nonsequence-specific complex of lac repressor indicates that in nonspecific complexes, the protein is still very mobile, and the interaction with the DNA is primarily through the backbone. In sequence-specific complexes, the protein often interacts with base atoms in the grooves, primarily the major groove. DNA-bound proteins also interact with each other and may add extra stabilization to the protein-DNA complex. This extra stabilization may be a good source of specificity for multiprotein regulatory complexes that form near eukaryotic genes.•α-helices are the most abundant elements involved in sequence-specific recognition of DNA. Different protein architectures and motifs used in DNA recognition usually involve α-helix. In some DNA-protein interactions, other peptide segments combine with helices. One of the nonhelical elements is a small flexible peptide that senses the sequence-dependent narrowing of the minor groove in homeodomain-containing transcription factors.•In prokaryotes, gene regulation by transcription factors occurs through interaction, either through contact or through competition, with the RNA polymerase. In eukaryotes, the DNA is packaged into nucleosomes and higher structures, blocking its access to the transcription machinery. Access control is the primary step, where eukaryotic transcription is regulated.•Artificial transcription factors have been created by mimicking many of the naturally occurring DNA-protein interactions and by totally synthetic molecules. Polyamides based on naturally occurring DNA-binding antibiotics, netropsin and distamycin, have proved to be effective. Peptide-based transcription factors mimicking naturally occurring transcription factors have also proved to be effective.•Transcription factors do not function in isolation in a cell. They cooperate with other transcription factors and regulatory proteins to form a gene regulatory network. Many different motifs are present. Motifs may give rise to unique properties having functional implications.