Computer-aided Design of a Catalytic Proton Channel
EMSL Project ID
42896
Abstract
The objective of the proposed research is to incorporate a rationally designed proton channel into homogeneous catalysts using advanced enzyme design methodology combined with superior molecular catalyst design. Proton channels, consisting of a series of proton relays, are essential for the rapid rates of proton reduction or hydrogen oxidation observed in enzymes such as hydrogenase, enzymes which are widely studied for their potential impact on energy and fuel storage. Hydrogenases (~90,000 Da) can reversibly oxidize or produce hydrogen with hydrogen production rates of 10,000 turnovers per second. This activity shuts down when the proton channel is deactivated. Small molecule catalysts are notably unable to match these rates. However, recent work by DuBois et al has shown rate enhancements of three to four orders of magnitude for hydrogen production and oxidation catalysts by placing a fixed proton relay in a synthetic hydrogenase mimic. Based on these observations, the hypothesis of the proposed research is that providing a proton channel to and from the active site is an essential characteristic necessary to further enhance the activity of synthetic analogs. We are requesting computational time to predict the 'best' peptide ligands to provide a stable scaffold and proton channel. These will then be synthesized and incorporated into nickel based hydrogenase catalyst mimics with already well-defined structure and activity. Catalysts will be designed using Rosetta, a structural prediction program with demonstrated success for designing de novo catalysts. Selecting the best structures predicted from this program, we will then perform MD on the most stable structures which also fit our requirement for a nearby relay. Further studies focus on the pKa of the relays, the distance between relays, the rigidity, structure and surrounding environment of the relay and ultimately the number of relays will be tested to guide experimental studies. The multistate empirical valance bond approach (MS-EVB) that captures the complex and collective proton motion (including the Grotthuss mechanism) in solvated environments will be used to predict which stabilized structures might perform better than others, as well as preferred proton transport pathways. This molecular level computational approach will allow us to develop a detailed understanding of proton relays, guiding experimental studies and providing insights into how they can enhance homogeneous catalysts, as well as how they function in enzyme systems.
Project Details
Project type
Exploratory Research
Start Date
2011-04-05
End Date
2012-04-08
Status
Closed
Released Data Link
Team
Principal Investigator