This book develops a statistical mechanical analysis of the stability of biological macromolecules. The author’s approach is valid both for the long time-scale needed for DNA bond disruption, and also for highly co-operative transitions needed to explain helix melting. A new theoretical approach for executing macromolecule calculations is developed. In particular, the author devises a method for describing chemical bond disruption in these large systems, which are then used to determine when the helix melts and how drugs can dissociate from the helix. Melting temperatures are found to be in excellent agreement with experimental observations. The book will be of interest to biomolecular dynamics researchers, especially to graduate students in biological physics, theoretical chemistry and molecular biology.