Ascorbic acid (AsA) and the nonsteroidal anti-inflammatory drug ibuprofen (IBU), adsorbed noncovalently on buckminsterfullerene C60 for its transdermal delivery, are investigated using Classical Molecular Dynamics and Density Functional Theory. Classical annealing is performed to explore the molecular configurations of both AsA and IBU adsorbed on C60, searching for optimal geometries. In particular, it is shown that IBU assumes two distinct adsorption geometries, giving rise to a two-level adsorption, leading to an extended anti-inflammatory delivery time. A vibrational analysis was also carried out for adsorbed IBU, depicting the IR and Raman spectra for both geometries. Furthermore, we investigated also the binding of IBU to human serum albumin (HSA) by using a fragmentation strategy together with a dispersion corrected exchange–correlation functional. Our computer simulations are valuable for a better understanding of the binding mechanism of AsA and IBU, looking for rational design and the development of novel drugs with improved potency.

We present the foundations of quantum mechanics required to describe atoms and molecules. Starting from classical mechanics, Schrödinger’s equation is introduced, while many-particle systems are approached using the Hartree and Hartree-Fock methods. Different chemical bond types are discussed in this context, namely: ionic, covalent, hydrogen, and van der Waals bonds. Classical molecular dynamics calculations are shown to be employed in the investigation of systems with up to millions of atoms, but quantum-level calculations are essential for an accurate description of chemical bond breaking and formation in biomolecular systems. The essentials of density functional theory (DFT), detailing the Hohenberg-Kohn theorems and the Kohn-Sham strategy, are presented. Distinct exchange-correlation functional approximations are shown with their limitations and advantages, including hybrid functionals. Finally, the description of a fragmentation strategy to apply quantum methods in the study of protein–ligand interactions is discussed.

A discussion on the relevance of protein–protein interactions (PPIs) in biochemistry and biophysics is presented, with the definitions of the proteome, interactome, and the classification of the PPIs. In particular, the essential role played by the Protein Data Bank (PDB) for the study of the PPIs is highlighted, as well as the use of classical molecular dynamics to improve the quality of PDB data and to test novel ligand geometries to improve drug efficiency. Focusing directly on the theoretical description of PPIs using physics, a detailed assessment of the dielectric function of proteins is carried out, with the definition of homogeneous and inhomogeneous dielectric constants and the description of the hydration layer of a solvated protein. Three strategies for the description of the inhomogeneous dielectric constant of proteins are shown, and a fragmentation procedure using density function theory (DFT) to obtain detailed energetic profiles of PPIs is depicted.