<p>Proteins are essential components of cells and are crucial for catalyzing reactions, signaling, recognition, motility, recycling, and structural stability. This diversity of function suggests that nature is only scratching the surface of protein functional space. Protein function is determined by structure, which in turn is determined predominantly by amino acid sequence. Protein design aims to explore protein sequence and conformational space to design novel proteins with new or improved function. The vast number of possible protein sequences makes exploring the space a challenging problem. </p><p>Computational structure-based protein design (CSPD) allows for the rational design of proteins. Because of the large search space, CSPD methods must balance search accuracy and modeling simplifications. We have developed algorithms that allow for the accurate and efficient search of protein conformational space. Specifically, we focus on algorithms that maintain provability, account for protein flexibility, and use ensemble-based rankings. We present several novel algorithms for incorporating improved flexibility into CSPD with continuous rotamers. We applied these algorithms to two biomedically important design problems. We designed peptide inhibitors of the cystic fibrosis agonist CAL that were able to restore function of the vital cystic fibrosis protein CFTR. We also designed improved HIV antibodies and nanobodies to combat HIV infections.</p> / Dissertation