The objective of this dissertation is to understand the binding mechanism between flexible macromolecules and guest species in solution using multiscale molecular modeling strategies, including: ab initio electronic structure theory, all-atom classical molecular dynamics simulations, coarse-grained molecular dynamics simulations, and statistical eld theory. A brief summary of the subsequent chapters in this thesis is provided. Chapters 2 - 7 and Appendix A are self-contained units complete with literature review and bibliography.