Computational tools for protein-DNA interactions

Interactions between DNA and proteins are central to living systems, and characterizing how and when they occur would greatly enhance our understanding of working genomes. We review the different computational problems associated with protein-DNA interactions and the various methods used to solve them. A wide range of topics is covered including physics-based models for direct and indirect recognition, identification of transcription factor binding sites, and methods to predict DNA-binding proteins. Our goal is to introduce this important problem domain to data mining researchers by identifying the key issues and challenges inherent to the area as well as provide directions for fruitful future research. Interactions between deoxyribonucleic acid (DNA) and proteins are widely recognized as central to living systems. These interactions come in a variety of forms including repair of damaged DNA and transcription of genes into RNA. More recently it has been found that, by binding to certain DNA segments, proteins can promote or repress the transcription of genes in the vicinity of the binding site. Proteins of this kind are referred to as transcription factors (TFs). The number of TFs in an organism appears to be related to the complexity of the underlying genome: as the number of of genes increases, the number of TFs increases according to a power law [1]. This many-fold increase of TFs appears to be required in order to manage transcription in higher organisms. Characterizing how and when protein-DNA interactions occur would greatly enhance our understanding of the genome at work. A full picture of the interactions will eventually allow characterization of which genes are transcribed at any given time in order for the organism to react dynamically to a changing environment. Protein-DNA interactions are studied both in the wet lab and computationally. Here a synergy exists: lab experiments provide data and problems for computational methods to solve while computation provides hypotheses which guide additional lab experiments. The goal of this article is to review three major areas of interest for computational studies of protein DNA interactions: (1) physics-based studies of protein-DNA interaction, (2) identification of transcription factor binding sites, and (3) identification of DNA-binding proteins. How Many Binding Proteins Exist? Accounts of how many DNA-binding proteins exist vary through the literature. Attention is particularly focused on transcription factors. Older sources estimated that 2-3% of a prokaryotic genome and 6-7% of a eukaryotic genome encodes DNA-binding proteins [2]. This number was taken from the automatic gene annotation tool PEDANT [3]. Though contemporary estimates of the number of transcription factors range as high as 10% of all mammalian genes [4], averaging across genomes in the DBD database [5] classifies 4.65% of Metazoan (animal) genes as transcription factors (806 genes per animal genome). [1]. According to gene ontology annotations in PEDANT, there are currently 1714 genes in the human genome identified as coding for DNA-binding proteins with 885 of them identified as