As such, these are very valuable tools in the assessment of the dynamics of such complexes on short (typically, picosecond to tens of nanosecond, occasionally microsecond) time scales. One of them are methods based on molecular dynamics (MD) simulations, provide detailed insights into the nature of ligand-protein interactions by representing the interacting species as a conformational ensemble that follows the laws of statistical thermodynamics. Two groups of computational methods, which are particularly useful in assessment of the thermodynamics of molecular recognition events, will be discussed. However, the deconvolution of the thermodynamic data and particular contributions is not a straightforward process in particular, assessing the entropic contributions is often very challenging. It plays a prominent role in the elucidation of the molecular mechanism of the binding phenomenon, and – through the link to structural data – enables the establishment of the structure-activity relationships, which may eventually lead to rational design. ![]() The information content provided by thermodynamic parameters is vast. Finally, I will address several practical aspects of assessing the thermodynamic parameters in molecular design, the bottlenecks of methods employed in such process, and the directions for future development. 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. I will discuss the applicability of these methods, the approximations behind them, and their limitations. ![]() 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. The second part is dedicated to methods applied to assess particular contributions, experimental as well as computational. solute-solvent interactions, solvent reorganisation). 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. This chapter is organised in the following way. 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. 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. Like any other spontaneous process, binding occurs only when it is associated with a negative Gibbs' free energy of binding ( Δ G), which may have differing thermodynamic signatures, varying from enthalpy- to entropy-driven. Binding between two interacting partners has both enthalpic (Δ H) and entropic (- TΔ S) components, which means the recognition event is associated with changes of both the structure and dynamics of each counterpart. ![]() Fundamentally, the biological processes rely on molecular organisation and recognition events. These interactions often display a remarkable degree of specificity and high affinity. 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. Biologically relevant macromolecules, such as proteins, do not operate as static, isolated entities.
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