Electrostatics and dynamics in molecular functions: a spectroscopic approach

Abstract

Understanding the physical basis of biomolecular processes is a continued pursuit in molecular biology. Non-covalent interactions (hydrogen bonding, hydrophobic interactions, electrostatic interactions, van der Waals interactions, etc.), fundamental to several biological processes, are exploited to regulate biomolecular functions involving molecular-recognition, protein folding, enzyme-catalysis and protein-protein interactions. In addition to these interactions, biological macromolecules have dynamic structures and the fluctuations of these structures are intimately related to their biological functions. Even at normal temperatures under thermal equilibrium conditions, the proteins are never at rest. Almost all biological processes involve structural and conformational changes in proteins. Proteins, in course of their transient interactions and conformational changes, behave in astounding ways, leading to enzyme catalysis, protein folding and misfolding, signaling and transport, charge transfer and energy relaxation and transduction. Proteins are the functional entities of cell and malfunction of proteins leads to several diseases. Therefore a cognitive understanding of interactions and dynamics, which play the central role in protein functions, is also crucial in the realm of drug discovery. Apart from understanding biomolecular functions, a feasible and economically viable synthetic strategy is required to obtain desired organics motifs of clinical importance. To this end, modern organic chemistry is longing for developing suitable catalysts to introduce chemical changes in reactions with a high level of precision. The core of catalyst design in homogeneous medium requires the knowledge of different kinds of interactions involved in catalysis along with the knowledge of the nature of fluctuating solvent medium. Various interactions, responsible in catalyzing reactions, are often non-covalent in nature. However, due to the lack of a general approach in describing/quantifying non-covalent interactions and dearth of our knowledge on the role of solvent dynamics in reaction mechanism, a unique catalyst design principle is still not known to date. Molecular functions are largely governed by intermolecular interactions. Usual theoretical approaches use some geometry and distance criteria to describe different intermolecular interactions. However often such descriptions lead to rise of confusion. Moreover, describing intermolecular interactions through geometric and distance constraints conceals the fact that such interactions can be explained and understood well by electrostatics. In this thesis, using electrostatics and dynamics, we have addressed few important challenges in biology and synthetic chemistry, the two principal contributing domains toward developing molecules relevant to the pharmaceutical industry. We have described how we have been able to surmount the challenges those came along the way.