A Comparative Dynamics Framework for Isolating Embedded Bacterial
Ferredoxin Domains within Larger Redox Enzymes
Abstract
Bacterial ferredoxins are small iron-sulfur binding proteins that
function as soluble electron shuttles between redox enzymes in the cell.
Their simple 2x(β-α-β) fold, central metabolic function, and ubiquity
across all kingdoms of life have led to the proposal that ferredoxins
were likely among the earliest proteins. Today, ferredoxin-like folds
are embedded in large, multidomain enzymes, suggesting ancient gene
duplication and fusion events. In some cases, these embedded domains may
have scant sequence or even structural homology to soluble counterparts,
challenging the use of traditional phylogenetic tools to establish
evolutionary relationships. In this study, we identify fragments of
bacterial ferredoxins within larger oxidoreductases by integrating
comparative sequence, structure, and dynamical attributes. Dynamics are
computed using an elastic network model and analyzed for similarity of
major normal modes. Using comparative dynamics, fragments of ferredoxin
domains are found within larger proteins, even in cases of limited
structural homology. This study also reveals a non-linear relationship
between dynamical and structural similarities, suggesting that protein
dynamics are more constrained than structure through evolutionary time.
We propose that dynamical similarity is indicative of functional
similarity. And, since nature selects for function, that the inclusion
of dynamical similarity, in addition to sequence and structure
similarities, provides a more robust framework for inferring homology.
Inclusion of dynamical attributes in comparative analysis will lead to a
greater understanding of the deep-time evolution of modern protein
nanomachines.