Radical S-adenosylmethionine maquette chemistry: Cx3Cx2C peptide coordinated redox active [4Fe–4S] clusters

Natural selection based on coordination chemistry: computational assessment of [4Fe–4S]-maquettes with non-coded amino acids

“…The overall Gibbs free energy values in table 2 (ΔG rxn ) clearly indicate that the cluster formation by ligand-exchange is spontaneous for all peptides regardless of the length of the thiolate side chain. This is in support of our observations of similar maquette formation yields for a wide range of cysteine containing peptides [20] with a variety of coded amino acids at intervening positions of the Cx 2 Cx 2 C motif. However, there are also significant differences in table 2 that show clear thermodynamic preference for the formation of the [4Fe-4S]-maquette with the coded Cys containing peptide CIACGAC.…”

“…This is in contrast to the experimental reconstitution yields of 29% and 6% for the reduced [4Fe-4S] + (CIACGAC) and [4Fe-4S] + (CGGCGGC) maquettes, respectively, reported in earlier studies [18,19]. Our recent experimental work indicates that under optimal experimental conditions in the presence of excess βME, 90 ± 10% reconstitution yields can be achieved for oxidized ([4Fe-4S] 2+ ) Fd-and radical SAMmaquettes, regardless of the amino acid sequence as long as three thiols are present in the vicinity of one another [20]. However, we observe similar lower yields (12 ± 5%) for the reduced ([4Fe-4S] 1+ ) Fd-and radical SAM-maquettes as reported in the literature [20].…”

“…Our recent experimental work indicates that under optimal experimental conditions in the presence of excess βME, 90 ± 10% reconstitution yields can be achieved for oxidized ([4Fe-4S] 2+ ) Fd-and radical SAMmaquettes, regardless of the amino acid sequence as long as three thiols are present in the vicinity of one another [20]. However, we observe similar lower yields (12 ± 5%) for the reduced ([4Fe-4S] 1+ ) Fd-and radical SAM-maquettes as reported in the literature [20]. Figure 2 summarizes the most pertinent information of the secondary structure analyses, which are the S … S distances and cluster nesting events.…”

“…In the context of emergence of life scenarios, spontaneous [Fe-S] cluster formation in aqueous solution can be a plausible way for facilitating electron transfer reactions by protocatalysts. Experimental reports [10,11,14,16,17,20] have expanded our awareness of which cysteine thiolate motifs can coordinate [Fe-S] clusters. Our work here highlights potential reasons for why cysteine, and not functional analogues of cysteine, may have been selected as the preferred [Fe-S] cluster ligands in nature.…”

“…This CxxCxxC motif was designed on the basis of the cluster binding amino acid sequence of bacterial ferredoxins (Fd). Recently, the Fd-maquette (FdM) work [17] was expanded to 8-mer peptides with the CxxxCxxC motif [20], which is the canonical cluster binding sequence for the [4Fe-4S] cluster [21] in radical S-adenosylmethionine (SAM) metalloenzymes [22]. These peptide bound metal clusters, termed [4Fe-4S]-maquettes, are valuable biomimetic models for structure/function studies.…”