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The structure of noncanonical amino acid (NCAA) side chains allows them to explore conformations inaccessible to canonical amino acids (CAAs). Peptides made of the D-enantiomers of amino acid backbones are resistant to proteolysis. The long term goal of this research is to adapt the current tools of computational protein design to create functional molecules be they proteins or not. In this thesis we have attempted the first steps toward this longer goal. The increased sequence and conformation space accessible to a protein during a design simulation when NCAAs are included, allows us to design tighter protein-protein interactions, with a higher degree of specificity. The computational protein design program Rosetta has been modified for compatibility with NCAAs. The use of knowledge-based potentials was the major hurdle as the potentials are based on statistics collected from known protein structures and few protein structures have been determined containing NCAAs. Using quantum mechanics (QM) calculations of the amino acids valine and isoleucine, with a helical conformation, we found an even distribution of rotamer preference. When that was used in rotamer recovery benchmarks, outperformed the knowledge-based potential that was biased because of long-range interactions imposed by the [alpha]-helical secondary structure. QM, although accurate and compatible with NCAAs was found to be too computationally expensive. We created a modified energy function that can evaluate the energy of both CAAs and NCAAs, where the knowledge-based energy potentials have been replaced with physically-based MM potentials that performs comparable to the stock energy function. We have developed methods to create rotamer libraries for both CAAs and NCAAs that are comparable to knowledge-based rotamer libraries. We have used these tools to create rotamer libraries for 88 different NCAAs that can now be used within Rosetta. The interface between calpain and the calpastatin peptide as well as the interface between HIV GP41 and the integration inhibitor, PIE12, developed by the Kay lab, has been redesigned using NCAAs to increase the binding affinity between the two pairs. The research has take protein design in a new direction and has enabled the development of novel protein interactions, and protein-like therapeutics.