ABSTRACT
The formation of the intermolecular complexes between ligands and their protein receptors plays an important role in regulating and controlling (activate/inhibit) cellular processes in biological systems. A prerequisite for the formation of the protein-ligand complex is the distinctive recognition of the ligand by its binding protein, which is commonly referred to as the molecular recognition problem. The essential point of molecular recognition is the complementarity between the ligand and its receptor, like complementarity of "lock and key"- the lock being the receptor and the key being the ligand that is recognized to give a defined ligand-receptor complex. It is the non-bonded intermolecular proteinligand interactions that are responsible for molecular recognition of a ligand by a protein. Therefore, an accurate and through understanding of non-bonded interactions is of great importance to decipher the mechanisms of molecular recognition of ligands by proteins. That is why high level quantum chemical analysis of intermolecular interactions has evolved into one of the challenging frontier areas of research in the field of theoretical and computational chemistry. In this lecture, I will start with an introduction to recent progress in the area of theoretical studies of non-bonded interactions, in particular recent breakthroughs in applying high level quantum mechanics methods to analyzing non-bonded interactions. Then, I will describe in details high level quantum chemical analyses of protein-ligand interactions that are responsible for molecular recognition of drugs in proteins. We have carried out a large-scale data mining of the Protein Data Bank to decipher molecular determinants for recognition of the FDA approved drugs in proteins. At first, a library of 3D drug-protein interaction motifs, including a wide spectrum of non-bonded interactions (hydrogen bonding, π-π stacking interactions, CH-π interactions and cation-π interactions), was established. Subsequently, a CCSD(T) level quantum chemical calculation was performed to quantify the energetics of drug binding. In addition to confirming the importance of the widely known hydrogen bonding, it was discovered that the aromatic π moieties of drugs played a crucial role in drug-target binding through π-π stacking and CH-π interactions.
BIOGRAPHY
Prof Xiche Hu graduated from Wuhan University with a BS and MS degree in Chemistry in 1982 and 1985, respectively. He received his PhD in Theoretical Chemistry from Wayne State University in 1991, and completed postdoctoral studies in computational chemistry and theoretical biophysics from University of California at Irvine and University of Illinois at Urbana-Champaign. He is an associate professor of chemistry at the University of Toledo, specializing in Advanced Biomolecular Modeling (Quantum chemical calculation of energetics of ligand-protein binding, and its application to molecular recognition of small molecular ligands/drugs in protein receptors) and Large Scale Biological Data Mining.