Molecular Recognition Mechanisms

The importance of molecular recognition in chemistry and biology is reflected in a recent upsurge in relevant research, promoted in particular by high-profile initiatives in this area in Europe, the USA and Japan. Although molecular recognition is necessarily microscopic in origin, its consequences are de facto macroscopic. Accordingly, a text that starts with intermolecular interactions between simple molecules and builds to a discussion of molecular recognition involving larger scale systems is timely. This book was planned with such a development in mind. The book begins with an elementary but rigorous account of the various types of forces between molecules. Chapter 2 is concerned with the hydrogen bond between pairs of simple molecules in the gas phase, with particular reference to the preferred relative orientation of the pair and the ease with which this can be distorted. This microscopic view continues in chapter 3 wherein the nature of interactions between solute molecules and solvents or between two or more solutes is examined from the experimental standpoint, with various types of spectroscopy providing the probe of the nature of the interactions. Molecular recognition is central to the catalysis of chemical reactions, especially when bonds are to be broken and formed under the severe con straint that a specific configuration is to result, as in the production of enan tiotopically pure compounds. This important topic is considered in chapter 4.

Molecular Toxinology has been consolidated as a scientific area focused on the intertwined description of several aspects of animal toxins. In an inquiring biotechnological world, animal toxins appear as an invaluable source for the discovery of therapeutic polypeptides. Animal toxins rely on specific chemical interactions with their partner molecule to exert their biological actions. The comprehension of how molecules interact and recognize their target is essential for the rational exploration of bioactive polypeptides as therapeutics. Investigation on the mechanism of molecular interaction and recognition offers a window of opportunity for the pharmaceutical industry and clinical medicine. Thus, this book brings examples of two interconnected themes - molecular recognition and toxinology concerning to the integration between analytical procedures and biomedical applications.

Molecular recognition is fundamentally important in biological chemistry. Nowadays, with the rapid development of computational technology and algorithm, molecular modeling has become a powerful tool in studying molecular recognition, such as exploring molecular interactions and understanding biological dynamic processes, making significant contributions to modern biology and drug discovery. The state-of-the-art techniques of computational chemistry and molecular modeling can be applied to study a wide range of chemical and biological systems of interest. This enables us to study structural details at the atomic level and obtain chemical/biological information which is not available by experimental measurements. This dissertation project focused on modeling the recognition mechanisms of biomolecules and their conjugated ligands. Multiple computational techniques, such as molecular dynamics simulation, enhanced sampling methods and free energy calculation were applied. The model systems included signaling domains (BRCT domain), kinase (p38 kinase), enzyme system (TRPS) and small biomolecular system (cyclodextrin). The details of protein-ligand interactions, including both enthalpic and entropic contribution within protein domain-phosphopeptide systems were investigated, based on which new inhibitors were proposed. Several enhanced sampling methods like accelerated molecular dynamics simulation, pathway search guided by internal motions (PSIM) and umbrella sampling, were applied to explore the dissociation pathway of kinase-ligand systems and the motions of kinase during dissociation process were studied both thermodynamically and kinetically, protein conformational rearrangement was found to differentiate slow and fast unbinding inhibitors, casting light on high efficacy inhibitor design. Furthermore, using full structural molecular modeling, we explored how the position of a single proton can change the overall protein dynamics and further activate or inactivate enzyme catalysis, elucidating the catalytic mechanism of TRPS. In addition, we performed systematically evaluation to the performance of umbrella sampling, investigated the influence of subtle changes in the dissociation pathways and conformational sampling methods that provide the initial conformations, paving way for future improvement of umbrella sampling. This project studies the details of receptor-ligand interaction and provides a more complete picture of molecular recognition.