Molecular Lego Based Organophosphatase Mimics
Abstract
The fundamental tools of life are enzymes – these are proteins that fold into three-dimensional shapes that contain pockets within which raw materials are selectively transformed into the building blocks of cells. Enzymes are remarkable catalysts - many of them transform molecules at the theoretical limit of speed (diffusion limited, as fast as the molecules encounter the catalyst), accelerating reactions that in the un-catalyzed case happen very slowly (half-lives from days to years to millions of years). Enzymes do so with extremely high fidelity, generating no waste and able to turn over billions of times – they are the definition of “green chemistry”. It is vital that chemists develop the ability to rationally design catalysts that work like enzymes - to create the raw materials that human beings need to live, and to break down the materials that are harmful to us. We will bring four research groups together and use two radical new technologies to achieve this. We have developed a molecular scaffold called “spiroligomers” that enable the synthesis of large, shape-programmable molecules that will display pockets and organize catalytic groups within the pockets to accelerate chemical reactions. We have also developed a compiled computer programming language that will enable the rational design of catalytic spiroligomers on large multi-processor supercomputers. Our overarching objective is to test the hypothesis that by properly positioning four or more functional groups and incorporating metals within a well defined, chiral, macromolecular pocket that together they can stabilize the transition state of a chemical reaction and demonstrate enzyme like rate-enhancements, stereoselectivities and regioselectivities while developing catalysts that hydrolyze deadly organophosphorous nerve agents. We seek to achieve this while developing a general technology to combine rational design with multiple rounds of targeted library synthesis, active catalyst selection and evolution of active catalysts to identify robust, enzyme-like catalysts for a wide-range of important reactions. In the base period (years 1-3), we will develop these technologies to design, synthesize and evaluate robust, abiotic, organophosphorous hydrolase metallo-enzyme mimics that will be developed to hydrolyze organophosphorous nerve agents. These catalysts could accelerate the hydrolysis of organophosphorous (OP) nerve agent compounds with the competency of organophosphate hydrolase enzymes, but unlike enzymes, spiroligomer bundles are extremely robust, they do not irreversibly denature under shifting temperature or solvent conditions, they are immune to proteases and they cannot raise a T-cell mediated immune response because they do not bind major histocompatibility enzymes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 13, 2016
- Source ID
- HDTRA11610047
Entities
People
- Christian E Schafmeister
Organizations
- Defense Threat Reduction Agency
- Temple University