Molecular Mechanism of Drug-DNA Intercalation and the Role of Water in Molecular Recognition

Abstract

The thesis entitled “Molecular Mechanism of Drug-DNA Intercalation and the Role of Water Entropy in Molecular Recognition” is focused on two aspects of molecular recognition process. One aspect is the study on the molecular mechanism of a molecular recognition process ‘intercalation’ and another aspect is the understanding of the ‘role of entropy of water molecule’ in molecular recognition processes using computational methods. DNA intercalation is one of the methods by which anti-cancer drugs function. Despite extensive experimental studies, molecular level understanding of the process is minimal. Extensive computational methods were used to probe into the molecular mechanism and the pathway intercalation of an anticancer agent proflavine to DNA. Detailed study revealed that the process happens by forming a pre-intercalative minor groove-bound state first, followed by subsequent intercalation into the DNA through the major groove. These studies brought evidence to support drug-induced cavity formation as opposed to natural fluctuation hypothesis for the process. Intercalation through the major groove is facilitated by absence of desolvation penalty. Therefore, water is plays an important role in the intercalation process. In reality, water plays an important role in various molecular recognition processes through both entropic and enthalpic contributions of which the first one, entropy, is difficult to estimate. Therefore, the estimation of entropy of individual water molecules at different locations around bio-molecular systems is highly important. A novel method was developed to calculate the rotational and translational entropy of individual water molecules and first applied to simple spherical hydrophobic and hydrophilic particles to show how negative to positive change in entropy happens when the size of hydrophobic solute is increased. Utilization of this method was extended to small ligand-protein complex to calculate the change in water entropy during the molecular recognition process.