Biological processes, such as gene regulation, DNA replication, or signal transduction pathways, frequently involve intermolecular recognition events associated with the interaction between two partners. For example, protein-DNA interactions are often observed in replication and repair machineries. Another example is the interaction between a protein and a small ligand activating transcription, as observed when cyclic AMP binds to, and activates, the protein CAP. This is an indication that the cell has to activate the transcription of certain genes.In many cases, the need for a fine regulation of the biological processes requires that intermolecular interactions are quite weak; in other cases they should be tight, and specific. A full understanding of the biological processes requires the understanding of how two partners recognize each other at a molecular and atomic level. It is then essential the study of the structure of the individual partners in the free and in the bound forms. The ability to determine high resolution structures in aqueous solution makes the use of NMR a suitable tool for studying biomolecular interactions at an atomic level.However, often this interaction is very complex, and just looking at the structures is not enough to get insight on how the complex is stabilized, or the various kind of complexes one molecule can form. A combined approach using structural, thermodynamic and genetic information is then important, in order to give a complete understanding of how the two partners recognize each other.We have studied the interaction between the lactose repressor of E. coli with DNA. Lactose is not the first energy source of the bacteria; the metabolism of lactose has to be tightly controlled, being used only if it is strictly necessary. Therefore, we anticipate a strict control over the expression of the genes of the lac operon, which is involved in the metabolism of lactose. As a consequence, the interaction between the lac repressor and the lac operator is tight and specific; it has been extensively studied using structural, genetic and thermodynamic approaches.The DNA binding domain of the lac repressor is located in the N-terminal segment of the protein, the so-called lac headpiece. Lac headpiece is a very flexible molecule. This property is certainly important for its capacity to interact with different DNA surfaces, and to adapt in order to maximize the interactions that stabilize the interface.Two different examples of protein-DNA adaptation are given in chapters 2 and 3 of this thesis. Chapter 2 describes the NMR structure of the lac headpiece bound to the lac operator Ol. The operator binding surfaces in the left and in the right sides are different. The interface in the left side is optimal, while the affinity towards the right side is lower; however, the lac headpiece adapts its structure in order to maximize the number of interactions. In chapter 3, the specificity of lac headpiece was altered by two mutations introduced in its recognition helix. Altering the DNA surface by the change of one base pair, compensated the changes imposed on the protein. A new altered specificity complex was obtained, and now, the lac headpiece mimics the DNA specificity of the gal repressor, the negative regulator of the gal operon. This altered specificity mutant of the lac repressor had been identified by Müller-Hill and co-workers in 1987. The NMR structure of the complex lead us to the identification of new protein-DNA interactions at the interface, and to the understanding of how the specificity for the DNA was changed. However, one interesting aspect of this mutant lac headpiece is still not fully understood: it binds tighter to non-operator DNA than the wild type does.The last chapter contains a study of hydrogen-deuterium exchange as an attempt to identify correlated motions within the most stable helices of the lac headpiece bound to DNA. Hydrogen-deuterium exchange of the amide protons is a unique technique, in the sense that it provides information about very slow molecular motions at the time scale of minutes or hours. It is shown that the exchange of the amide protons of the recognition helix of the lac headpiece bound to DNA occurs by a cooperative unfolding mechanism. To our knowledge, it is the first time this has been shown for an alfha-helix.