Ilya A. Balabin

The Nature of Aqueous Tunneling Pathways Between Electron-Transfer Proteins

Structured water molecules near redox cofactors were found recently to accelerate electron-transfer (ET) kinetics in several systems. Theoretical study of interprotein electron transfer across an aqueous interface reveals three distinctive electronic coupling mechanisms that we describe here: (i) a protein-mediated regime when the two proteins are in van der Waals contact; (ii) a structured water-mediated regime featuring anomalously weak distance decay at relatively close protein-protein contact distances; and (iii) a bulk water–mediated regime at large distances. Our analysis explains a range of otherwise puzzling biological ET kinetic data and provides a framework for including explicit water-mediated tunneling effects on ET kinetics.

Dynamics of Electron Transfer Pathways in Cytochrome c Oxidase

Cytochrome c oxidase mediates the final step of electron transfer reactions in the respiratory chain, catalyzing the transfer between cytochrome c and the molecular oxygen and concomitantly pumping protons across the inner mitochondrial membrane. We investigate the electron transfer reactions in cytochrome c oxidase, particularly the control of the effective electronic coupling by the nuclear thermal motion. The effective coupling is calculated using the Greens function technique with an extended Huckel level electronic Hamiltonian, combined with all-atom molecular dynamics of the protein in a native (membrane and solvent) environment. The effective coupling between Cu(A) and heme a is found to be dominated by the pathway that starts from His(B204). The coupling between heme a and heme a(3) is dominated by a through-space jump between the two heme rings rather than by covalent pathways. In the both steps, the effective electronic coupling is robust to the thermal nuclear vibrations, thereby providing fast and efficient electron transfer.

Coarse-grained modeling of allosteric regulation in protein receptors

Allosteric regulation provides highly specific ligand recognition and signaling by transmembrane protein receptors. Unlike functions of protein molecular machines that rely on large-scale conformational transitions, signal transduction in receptors appears to be mediated by more subtle structural motions that are difficult to identify. We describe a theoretical model for allosteric regulation in receptors that addresses a fundamental riddle of signaling: What are the structural origins of the receptor agonism (specific signaling response to ligand binding)? The model suggests that different signaling pathways in bovine rhodopsin or human β2-adrenergic receptor can be mediated by specific structural motions in the receptors. We discuss implications for understanding the receptor agonism, particularly the recently observed “biased agonism” (selected activation of specific signaling pathways), and for developing rational structure-based drug-design strategies.

Heme–copper oxidases use tunneling pathways

Electron transfer (ET) reactions in bioenergetics move electrons 10 A and more between redox cofactors through insulating protein (1). Nowhere else does the wave nature of matter control a biological event in a more striking way: These shifting electrons tunnel quantum mechanically from donor to acceptor. Nature uses the physics of electron tunneling for good reason: Delocalized charge would dissipate energy and induce collateral redox damage. As described in a recent issue of PNAS (2), new studies of electron tunneling between hemes in the quinol-oxidizing cytochrome bo 3, a heme–copper oxidase in the same family as cytochrome c oxidase, find that a specific tunneling conduit, or tunneling pathway, mediates the electron flow. This experiment, which shows that a dominant coupling pathway controls a physiological ET reaction, reveals the limitations of coarse-grained (average medium) models for protein electron tunneling and indicates why atomic-resolution descriptions can be essential. The perspective emerging from this study will help to determine how evolution acts on the molecular structure of electron tunneling pathways in the biological ET chains.

Understanding structural and dynamic control of the effective electronic coupling in protein electron transfer

We present a general framework for analyzing how molecular structure and dynamics control the effective tunneling coupling in electron transfer reactions. Using combined molecular dynamics and electronic structure calculations, we explore four principal issues that could not be quantitatively addressed at the Pathways level: sensitivity to the choice of the electronic Hamiltonian, interference among pathways, sensitivity to the electron transfer bridge conformation and modulation by the dynamical motion of the bridge. To be able to categorize the electronic orbital interactions, to identify the most relevant ones and to investigate their sensitivity to the bridge structure and dynamics, we introduce the dynamic overlap-coupling (S – H) maps. Using this framework, we identify dominant pathways mediated by these interactions and analyze the effects of the interference among them on the effective coupling. This approach provides a clear view of how the bridge structure and dynamics controls the effective cou...