Identification of n?n Interactions in Bioactive Conformations Ligands using structural and Computational Studies

Abstract

n→π* interactions (O→C=O) are found in abundance along the protein main-chain and have been shown to play an important role in the protein structure formation and stabilization. In this study, we extend the realm of n→π* interactions to bioactive conformation of ligands. Structural and computational analyses of a heterogeneous dataset of 250 bioactive conformers from PDB showed that, 11 different type of n→π* interactions (e.g. O→C=C, O→C=O, N→C=C, S→C=C, F→C=O, Cl→C=C etc.) are potentially present intramolecularly along with other close noncovalent interactions. Five different lone pair n containing atoms – O, N, S, F, Cl and four different π* antibonding orbital containing groups →C=C,→C=O, →C=N,→N=C, have been observed to participate in n→π* interactions. The n and π* have their origins in protein main-chain, amino acid side-chain, diverse ligand functional groups, aromatic rings and heteroaromatic rings. Most of these interactions follow the Bürgi-Dunitz trajectory with a mean distance (d) and angle (θ) of 3.06±0.17Å and 118.22±20.95° respectively. NBO calculations showed these interactions to be weak interactions and had mean strength of ~0.3 kcal/mol. Only in two cases, these interactions are found to occur simultaneously with hydrogen bond as observed in proteins. n→π* interactions in bioactive conformers are not as widespread as in proteins. Similar to their role in proteins, we hypothesize that, n→π* interactions would be another specific type of noncovalent force involved in the orientation of the bioactive conformers in the active binding site of protein. Their inclusion in the computational force fields and scoring functions could improve the correlation between experimental and predicted binding affinities of the ligand.