Disentangling First and Second Sphere Effects in Iron–Sulfur Cubanes

Cubane-type iron–sulfur clusters (Fe4S4) are some of the most versatile metallocofactors and,
as such, among
multiple functions, primarily responsible for mediating challenging
electron transfers (ETs). Their efficient ET chemistry is enabled
by a conflated interplay of cofactor–protein interactions,
which can be categorized into the covalent first (1°) sphere
ones and the noncovalent second (2°) sphere ones. The latter
have remained particularly elusive, as they are difficult to observe
and assess directly and independently. Accordingly, our understanding
of these effects is hampered by their entangled nature. To address
this, we herein leverage a systematic series of synthetic Fe4S4 complexes, which allows spectroscopically investigating
2° sphere electrostatic interactions and covalent 1° sphere
interactions separately from one another. We expand the study of 1°
sphere interactions with a histidine-type ligand in [Fe4S4]1+ complexes to the [Fe4S4]2+ and [Fe4S4]3+ oxidation states, supporting the notion that 1° sphere interactions
“fine-tune” the electronic/magnetic structure of these
systems in a manner that persists at ambient temperatures. In contrast,
scrutinizing the 2° sphere electric dipolar interactions in [Fe4S4]1+,2+,3+ complexes revealed that
although similar effects are observable at extremely low temperatures,
no significant alteration of the clusters’ gross electronic/magnetic
structure persists at the temperatures relevant to enzyme function.
These results thus not only systematically catalogue the influence
of 1° sphere covalent and 2° sphere electrostatic interactions
on the observables and properties of Fe4S4 complexes,
but also establish a clear energetic distinction between the two.
As such, they will facilitate identifying the elusive 2° sphere
interactions in biological systems, while also strengthening our biophysical
understanding of structure–function relationships in Fe4S4 cofactors.