Modeling Electron Transfer Thermodynamics in Protein Complexes: Interaction between Two Cytochromes c3

Abstract

Redox protein complexes between type I and type II tetraheme cytochromes c3 from Desulfovibrio vulgaris Hildenborough are here analyzed using theoretical methodologies. Various complexes were generated using rigid-body docking techniques, and the two lowest energy complexes (1 and 2) were relaxed using molecular dynamics simulations with explicit solvent and subjected to further characterization. Complex 1 corresponds to an interaction between hemes I from both cytochromes c3. Complex 2 corresponds to an interaction between the heme IV from type I and the heme I from type II cytochrome c 3. Binding free energy calculations using molecular mechanics, Poisson-Boltzmann, and surface accessibility methods show that complex 2 is more stable than complex 1. Thermodynamic calculations on complex 2 show that complex formation induces changes in the reduction potential of both cytochromes c3, but the changes are larger in the type I cytochrome c3 (the largest one occurring on heme IV, of ∼80 mV). These changes are sufficient to invert the global titration curves of both cytochromes, generating directionally in electron transfer from type I to type II cytochrome c3, a phenomenon of obvious thermodynamic origin and consequences, but also with kinetic implications. The existence of processes like this occurring at complex formation may constitute a natural design of efficient redox chains.