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Biologically relevant macromolecules, such as proteins, do not operate as static, isolated entities. On the contrary, they are involved in numerous interactions with other species, such as proteins, nucleic acid, membranes, small molecule ligands, and also, critically, solvent molecules. These interactions often display a remarkable degree of specificity and high affinity. Fundamentally, the biological processes rely on molecular organisation and recognition events. Binding between two interacting partners has both enthalpic (H) and entropic (-TS) components, which means the recognition event is associated with changes of both the structure and dynamics of each counterpart. Like any other spontaneous process, binding occurs only when it is associated with a negative Gibbs' free energy of binding ( G  ), which may have differing thermodynamic signatures, varying from enthalpyto entropy-driven. Thus, the understanding of the forces driving the recognition and interaction require a detailed description of the binding thermodynamics, and a correlation of the thermodynamic parameters with the structures of interacting partners. Such an understanding of the nature of the recognition phenomena is of a great importance for medicinal chemistry and material research, since it enables truly rational structure-based molecular design. This chapter is organised in the following way. The first part of it introduces general principles which govern macromolecular associations under equilibrium conditions: the free energy of binding and its enthalpic and entropic components, the contributions from both interacting partners, interaction energy of the association, and specific types of interactions – such as hydrogen bonding or van der Waals interactions, ligand and protein flexibility, and ultimately solvent effects (e.g. solute-solvent interactions, solvent reorganisation). The second part is dedicated to methods applied to assess particular contributions, experimental as well as computational. Specifically, there will be a focus on isothermal titrational calorimetry (ITC), solution nuclear magnetic resonance (NMR), and a discussion of computational approaches to the estimation of enthalpic and entropic contributions to the binding free energy. I will discuss the applicability of these methods, the approximations behind them, and their limitations. In the third part of this chapter, I will provide the reader several examples of ligand-protein interactions and focus on the forces driving the associations, which can be very different from case to case. Finally, I will address several practical aspects of assessing the thermodynamic parameters in molecular design, the

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design