Computational Redesign of Phosphotriesterase

Computational Redesign of Phosphotriesterase Product: Research Proposal Education Level: PhD\Doctorate References: 11 English: US Paper Length: 18 pages\4950 words Deadline: November 20, 2014 Add ons: 1 page summary & PPT Slides of 5 count Details: (this is a research proposal) ABSTRACT: Computational enzyme design is a fairly recent field with a growing repertoire of successes. Here the aim is to design versions of phosphotriesterase (PTE) to efficiently and robustly, degrade substrates other than the native substrate paraoxon. Other approaches, such as directed evolution, have resulted in only marginal improvements to PTE. These methods require many rounds of random mutagenesis followed by screening to select more active candidates. Our approach is to employ rational design methods in silico to re-engineer different versions of PTE. Quantum and molecular mechanical methods will be used to build idealized active site cores, around which Rosetta design methods will be applied to select amino acid configurations to support the transition state geometry, possibly including non-canonical amino acids. Finally, molecular dynamics simulations will virtually screen each candidate for viability. An effective methodology for modifying PTE would allow custom enzymes to be constructed to degrade a variety of organophosphate ligands which include pesticides and nerve agent chemical weapons.