Onuchic 9316186 The focus of this research program is to understand under precisely what conditions electron tunneling in proteins can be explained by our Pathways approach, and when explicit multiple pathways become important. To address these questions we will implement our new suite software package, Greenpath, which is based on our SGF method. Using the new software, we will be able to develop the concept of pathway families. In the limit that the protein can be represented by a few independent pathway families, a reduced or simplified representation of the protein (renormalized protein) will become possible for ET. This renormalized protein will include all the relevant details of the protein environment that will influence the value of TDA. In the opposite limit, when large interferences between families of pathways become important, the description of the protein environment as a homogeneous medium will become valid (details of the structure will not be important). The simple model of TDA decaying exponentially with the direct distance separation between redox sites will become valid. (However this decay factor may vary for different proteins.) This strategy will be tested on ruthenium-modified cytochrome c and myoglobin. A larger number of proteins is necessary to understand why some structures may be understood with a few pathway families while other ones may not. Therefore, myoglobin and cytochrome c are just the first two proteins to be analyzed using the proposed procedure. Several other proteins will also be analyzed: cytochrome b5 and cytochrome C551 (alpha-helical), plastocyanin and azurin (beta-barrel), and HiPIP, for example. If successful, this strategy will become a very powerful tool for the study and design of new electron transfer proteins. The method will be expanded to investigate electron transfer in protein complexes. Studies will focus on the following complexes: cytochrome c- cytochrome c peroxidase and photosynthetic reaction center- cytochrome c. Also, since the tunneling matrix element is affected by protein internal water molecules and protein motions, improvements to the method will be included to account for these effects. %%% Electron transfer processes are ubiquitous in chemistry, biology and physics. In biology, these reactions occur in the key bioenergetics processes of photosynthesis and oxidative phosphorylation. The rates of these reactions are extraordinarily sensitive to the chemistry of the bridge coupling the sites for the electron. Our main goal is to create a theoretical framework for understanding these electron transfer reactions and for designing new molecules with performance analogous to the biological ones. The success of our model and software Pathways opens up new methods for designing electron transfer proteins. The power of predicting experimental data speaks for itself. To the best of my knowledge, Pathways is the only theoretical approach for biological reaction rate design, other than qualitative structural (steric effects) or electrostatic calculations. Yet, this is just the starting point. We are very optimistic about the growth of new increasingly sophisticated methods following on the developments of Pathways. These new techniques will give rise to a new software package Greenpath that is the main goal of the proposed work. Using these new techniques, we will be able to answer several existing questions not addressed by Pathways (or other methods). We will also create a powerful set of tools to interpret native biological electron transfer systems and to aid in the design of new electron transfer proteins. ***
