Protein loops, the "nonregular" structures connecting secondary structures, have been considered the source of heterogeneity responsible for protein function. Recent studies suggest that molecular flexibility and the dipeptide makeup of proteins are ultimately responsible for protein structure and the rise of genetics. Similarly, folding speed, which is correlated to flexibility, was found to increase during protein evolution. Since loop flexibility maybe a major link between structure, function and evolution, its study at genomic level could unlock prediction of evolutionary trajectories of macromolecules and facilitate advances in synthetic biology and translational medicine. My dissertation research aims to address the following: (1) determine history in protein structures using phylogenetic and graph-theoretical frameworks that link structure and flexible loop regions, (2) study patterns of flexibility and function in the three domains of life as well as viruses, and (3) determine loop motions that are associated with functional diversity using molecular dynamic (MD) simulation. In order to achieve these objectives, we make use of advanced methods of phylogenomic analysis to dissect the genomic impact of the combinatorial rearrangement of loops and domains and patterns of molecular accretion in the emergence of molecular functions. Additionally, we use NCSA Blue Waters, to integrate biophysics and genomic evolution by linking changes unfolding at nanosecond to microsecond levels with those spanning billions of years of protein history. In summary, our study weaves together, the paradigms of genomics, proteomics and biophysics.