Protein electron transfer: is biology (thermo)dynamic?

Abstract

Simple physical mechanisms are behind the flow of energy in all forms of life. Energy comes to living systems through electrons occupying high-energy states, either from food (respiratory chains) or from light (photosynthesis). This energy is transformed into the cross-membrane proton-motive force that eventually drives all biochemistry of the cell. Life's ability to transfer electrons over large distances with nearly zero loss of free energy is puzzling and has not been accomplished in synthetic systems. The focus of this review is on how this energetic efficiency is realized. General physical mechanisms and interactions that allow proteins to fold into compact water-soluble structures are also responsible for a rugged landscape of energy states and a broad distribution of relaxation times. Specific to a protein as a fluctuating thermal bath is the protein-water interface, which is heterogeneous both dynamically and structurally. The spectrum of interfacial fluctuations is a consequence of protein's elastic flexibility combined with a high density of surface charges polarizing water dipoles into surface nanodomains. Electrostatics is critical to the protein function and the relevant questions are: (i) What is the spectrum of interfacial electrostatic fluctuations? (ii) Does the interfacial biological water produce electrostatic signatures specific to proteins? (iii) How is protein-mediated chemistry affected by electrostatics? These questions connect the fluctuation spectrum to the dynamical control of chemical reactivity, i.e. the dependence of the activation free energy of the reaction on the dynamics of the bath. Ergodicity is often broken in protein-driven reactions and thermodynamic free energies become irrelevant. Continuous ergodicity breaking in a dense spectrum of relaxation times requires using dynamically restricted ensembles to calculate statistical averages. When applied to the calculation of the rates, this formalism leads to the nonergodic activated kinetics, which extends the transition-state theory to dynamically dispersive media. Releasing the grip of thermodynamics in kinetic calculations through nonergodicity provides the mechanism for an efficient optimization between reaction rates and the spectrum of relaxation times of the protein-water thermal bath. Bath dynamics, it appears, play as important role as the free energy in optimizing biology's performance.

Direct Measurement of Charge Regulation in Metalloprotein Electron Transfer

“…Considering the importance of solvent reorganization in λ T ,5 we suspect that changes in the protonation of some residues might occur with ET, and make non‐negligible contributions to λ T . Insofar as the fluctuation in the p K a value of a residue might contribute to λ T , we presume that it contributes primarily to λ o (except for the acidic H 2 O bound to Fe 3+ in Mb, which dissociates upon ET and would contribute to λ i ).…”

High-resolution electrochemical STM of redox metalloproteins

“…The local structure of water molecules at interfaces is, for example, well known to be partly ordered. Recently, Matyushov et al [47][48][49][50] have explored how experimentally rather smaller reorganisation energies than expected from atomistic simulations might be explained, examining the case [47] of cytochrome c. They extend the Marcus/Gerischer model to distinguish between two types of reorganisation energy representing medium polarisation and (a typically large) thermal fluctuation contribution, the latter being linked to a heterogeneous region surrounding the protein cofactor. The arguments are interesting and would perhaps apply a fortiori to the local geometry of the EC-STM set up.…”

Activated kinetics in a nonequilibrium thermal bath

“…This inequality implies greater thermal agitation within the system than work extracted in response to an external force. This general result has important consequences for energy chains of biology where barriers for moving electrons and, potentially, for other enzymatic reactions, are lowered by such excessive fluctuations (10). Because the nanometer length scale required for creating nonequilibrium states of the reactants and products is becoming increasingly accessible to experimentation, the natural question for this new emerging chemistry is how to describe chemical reactions at such conditions.…”

“…When the length scale for the temperature change becomes comparable to the distance between the donor and acceptor, one has to question the applicability of the Boltzmann distribution as the way to define probabilities of system configurations. Although this proposal seems to be far-reaching at first glance, it is perhaps quite common in electron transfer reactions occurring in biology's energy chains (10). Proteins demonstrate a broad distribution of relaxation time scales.…”

“…The reaction enthalpy, given as the slope of the Arrhenius plot, is significantly reduced for the nonequilibrium bath. In addition, a slight curvature develops as a signature of a generally non-Arrhenius rate law in nonequilibrium systems (10).…”