Non-covalent interactions in ligand-receptor complexes. A study by electron charge density

ANGELINA, EMILIO; ANDUJAR, S; SUVIRE, F. D.; ENRIZ, D. R.; PERUCHENA, N. M.

Foz do Iguazu

Congreso; 12th Latin American Conference on Physical Organic Chemistry; 2013

Latin American Physical Organic Chemistry

One of the most motivating fact for study of the non-covalent interactions is that they are responsible for the structure and dynamics and, consequently, also the function of biological macromolecules. Thus, for example the interaction of a hormone with a receptor can produce a cascade of processes many of them closely related to the formation or rupture of non-covalent interactions. Then, the understanding of non-covalent interactions in biomolecules and their microsolvated clusters in the gas phase, constituted a bulky challenge. In addition, as the non covalent interactions become weaker than covalent interactions they are more difficult to describe properly. However, recent advances in computational calculation of the electron charge density make possible the proper description of the three-dimensional network of bonding and non bonding interactions in the context of the quantum theory of atoms in molecules (QTAIM). In fact, nowdays it is well know that the stacking of aromatic ring of amino acids in proteins is evidently much more important than it has been previously believed and, indeed, can form one of the dominant stabilizing contributions.    In this work, several selected conformations of molecular complexes, obtained from our ¡°reduced model system¡± 1 (with only 13 amino acids of the active site of the receptor) were used as input by the calculation of the charge density. Single point calculations were realized with Gaussian 03 employing a hybrid B3LYP functional and 6-31+G(d,p) as a basis set.    The results show that the interactions of the catechol OH DA in differentconformations of the complex DA-RD2, determine the decrease (or increase) of the electron density on the aromatic ringof DA. In turn, the electronic population of the aromatic ring of DA, defines its orientation within the active site and the type of interactions that are established with the aromatic rings of the receptor. The stacking-type interactions between the C¥ð¨ù C¥ð ring and the aromatic rings DA receptor, are favored when onthe ring ofDA is diminished. Conversely, when the electronic charge on the ring of DA is high, this tends to orient perpendicular(T-shaped) to the plane of the aromatic rings of the receiver, verifying ¥ð- interactions C-H...C¥ð type.   Summarizing, in this paper we reported the results obtained by charge density analysis of the network of non covalent interactions present in the active site  of the receptor (in relevant conformations of L-R complexes). We believe that our results could help in the understanding the contribution that a particular amino acid present in the active site of the receptor could make on the network of weak non covalent interactions and this knowledge can serve as a guide for the design of new ligands for this receptor.   1 Andujar et al. Journal of Chemical Information and Modelling, 2012, 52, 99-112.