Abstract
Long-range electron tunneling through metalloproteins is facilitated by evolutionary tuning of donor–acceptor electronic couplings, formal electrochemical potentials, and active-site reorganization energies. Although the minimal frustration of the folding landscape enables this tuning, residual frustration in the vicinity of the metallocofactor can allow conformational fluctuations required for protein function. We show here that the constrained copper site in wild-type azurin is governed by an intricate pattern of minimally frustrated local and distant interactions that together enable rapid electron flow to and from the protein. In contrast, sluggish electron transfer reactions (unfavorable reorganization energies) of active-site azurin variants are attributable to increased frustration near to as well as distant from the copper site, along with an exaggerated oxidation-state dependence of both minimally and highly frustrated interaction patterns.
Highlights
Biological electron transfer reactions, the core of the cell’s energy economy, generally require the reorganization of the protein environment surrounding a metal ion or a co-factor.[1−4] The specificity of the structural fold enables the evolutionary tuning of thermodynamic reduction potentials, both directly, through constraining the local coordination geometry of the metal with specific amino acid ligands and through electrostatic interactions with more distant residues
We explore how tuning the frustration of the energy landscape links to the electron flow in azurin, a wellstudied blue copper protein.[8−21] To quantify and locate sites of conflicting interactions in azurin, we use atomistic frustration analysis, based on algorithms inspired by energy landscape theory.[6,7]
Copper coordination in azurin can be described as distorted trigonal pyramidal (Figure S4), which is a compromise between the preferred coordination geometries for Cu(I) and Cu(II), but it is believed to favor Cu(I).[4]
Summary
Biological electron transfer reactions, the core of the cell’s energy economy, generally require the reorganization of the protein environment surrounding a metal ion or a co-factor.[1−4] The specificity of the structural fold enables the evolutionary tuning of thermodynamic reduction potentials, both directly, through constraining the local coordination geometry of the metal with specific amino acid ligands and through electrostatic interactions with more distant residues. The rate of electron transfer depends on the barrier for reorganizing the protein environment, which involves changing from one protein conformation, solvating the initial charge state of the ion, to the one solvating the final state This reorganization energy is not determined by the single structure of the protein but by the energy landscape of available protein conformations solvating the co-factor. Some locally frustrated interactions can be tolerated by evolution but at the cost of proliferating thermally accessible substrates on the energy landscape of the functional protein Such local frustration substantially increases active-site redox reorganization energies, turning off the distant electron tunneling reactions required for function
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