De novo computational design of catalytic peptide and peptoid macrocycles
Abstract
Discover fundamental computational design methods to iteratively produce and optimize small macrocyclic catalysts capable of neutralizing chemical warfare agents. We will integrate three recent developments in our laboratory: the ability to design macrocyclic compounds with unnatural amino acids and backbones with high accuracy; the ability to design catalytic sites which irreversibly bind to organophosphate (OP) compounds; and the understanding of how to create iterative design-build-test-learn pipelines to systematically improve our designs. Recently, significant progress has been made in our macrocycle design efforts, including the near-atomically accurate design of cyclic peptides that accommodate desired coordination states of metal centers. In Base Period Years 1-3 we will build on these advances to pursue the systematic discovery of design methods for producing highly stable macrocyclic peptide and peptoid compounds (<5KDa) with activated nucleophiles that can achieve single turnover capture (Track 1) and multiple turnover hydrolysis (Track 12) and single turnover capture (Track 2) of organophosphate (OP) compounds. We will test numerous catalytic hypotheses and optimize macrocycle activity through large-scale design-build-test-learn iterations. We will test catalytic hypotheses and optimize macrocycle activity through large-scale design -build-test-learn iterations. By the end Base Period Years 1-3, we expect to arrive at a new understanding of the basic principles for designing macrocycles that catalyze OP capture and water mediated multiple turnover reactions in solutions containing organic solvents at ambient temperatures. In Option Years 4 and 5, we will continue to discover fundamental improvements in the computational design of catalytic macrocycles and tune our catalysis for enhanced suicide capture and water mediate hydrolysis of VX and other DoD relevant organophosphate nerve toxins.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 01, 2019
- Source ID
- HDTRA11910003
Entities
People
- David Baker
Organizations
- Defense Threat Reduction Agency
- University of Washington