Computational protein design: assessment and applications

Indiana University-Purdue University Indianapolis (IUPUI)Computational protein design aims at designing amino acid sequences that can fold into a target structure and perform a desired function. Many computational design methods have been developed and their applications have been successful during past two decades. However, the success rate of protein design remains too low to be of a useful tool by biochemists whom are not an expert of computational biology. In this dissertation, we first developed novel computational assessment techniques to assess several state-of-the-art computational techniques. We found that significant progresses were made in several important measures by two new scoring functions from RosettaDesign and from OSCAR-design, respectively. We also developed the first machine-learning technique called SPIN that predicts a sequence profile compatible to a given structure with a novel nonlocal energy-based feature. The accuracy of predicted sequences is comparable to RosettaDesign in term of sequence identity to wild type sequences. In the last two application chapters, we have designed self-inhibitory peptides of Escherichia coli methionine aminopeptidase (EcMetAP) and de novo designed barstar. Several peptides were confirmed inhibition of EcMetAP at the micromole-range 50% inhibitory concentration. Meanwhile, the assessment of designed barstar sequences indicates the improvement of OSCAR-design over RosettaDesign