The focus of this proposal is to understand the basis for the specific structure/function relationship in complex protein reactions by examining differences and similarities between the 'same' protein from different organisms. This approach will help to understand the natural variation in protein structure, function and other properties between different isoforms or different species and is a necessary complement to the study of site-directed mutants of a single protein. This effort is part of a long-term interest in the use of EPR as a structural probe and draws on experience in developing and applying innovative EPR methods for answering specific biological and physical questions. This work will provide insights into the bioenergetically important cytochrome bc-type complex and the metabolically important eukaryotic cytochrome P450 enzymes that could lead to new, highly-selective drugs and antibiotics exploiting differences between these proteins in different organisms or between different isoforms in humans. The methods developed in carrying out this work will be broadly applicable to other membrane proteins and other protein complexes.