Structural Determinants of Redox Conduction Favor Robustness over Tunability in Microbial Cytochrome Nanowires

ABSTRACT Helical homopolymers of multiheme cytochromes catalyze biogeochemically significant electron transfers with a reported 10 3 -fold variation in conductivity. Herein, classical molecular dynamics and hybrid quantum/classical molecular mechanics are used to elucidate the structural determinants of the redox potentials and conductivities of the tetra-, hexa-, and octaheme outer-membrane cytochromes E, S, and Z, respectively, from Geobacter sulfurreducens . Second-sphere electrostatic interactions acting on minimally polarized heme centers are found to regulate redox potentials over a computed 0.5-V range. However, the energetics of redox conduction are largely robust to the structural diversity: Single-step electronic couplings (⟨H mn ⟩), reaction free energies , and reorganization energies (λ mn ) are always respectively <|0.026|, <|0.26|, and between 0.5 – 1.0 eV. With these conserved parameter ranges, redox conductivity differed by less than a factor of 10 among the ‘nanowires’ and is sufficient to meet the demands of cellular respiration if 10 2 – 10 3 ‘nanowires’ are expressed. The ‘nanowires’ are proposed to be differentiated by the protein packaging to interface with a great variety of environments, and not by conductivity, because the rate-limiting electron transfers are elsewhere in the respiratory process. Conducting-probe atomic force microscopy measurements that find conductivities 10 3 -10 6 -fold more than cellular demands are suggested to report on functionality that is either not used or not accessible under physiological conditions. The experimentally measured difference in conductivity between Omc- S and Z is suggested to not be an intrinsic feature of the CryoEM-resolved structures.