Tristhiolato Pseudopeptides Bind Arsenic(III) in an AsS₃ Coordination Environment Imitating Metalloid Binding Sites in Proteins

Abstract

The AsIII binding of two NTA-based tripodal pseudopeptides, possessing three cysteine (ligand L1 ) or d-penicillamine residues (ligand L2 ) as potential coordinating groups for soft semimetals or metal ions, was studied by experimental (UV, CD, NMR, and ESI-MS) and theoretical (DFT) methods. All of the experimental data, obtained with the variation of the AsIII:ligand concentration ratios or pH values in some instances, evidence the exclusive formation of species with an AsS3-type coordination mode. The UV-monitored titration of the ligands with arsenous acid at pH = 7.0 provided an absorbance data set that allowed for the determination of apparent stability constants of the forming species. The obtained stabilities (logK′ = 5.26 (AsL1 ) and logK′ = 3.04 (AsL2 )) reflect high affinities, especially for the sterically less restricted cysteine derivative. DFT calculated structures correlate well with the spectroscopic results and, in line with the 1H NMR data, indicate a preference for the all-endo conformers resembling the AsIII environment at the semimetal binding sites in various metalloproteins.

AsIII Selectively Induces a Disorder-to-Order Transition in the Metalloid Binding Region of the AfArsR Protein

“…The interaction of arsenous acid (As III ) and the peptide (Figure ) was studied at different pH values by recording the UV-absorption spectra of the ligand at gradually increasing As III : L concentration ratios (Figures and S1). The gradually increasing absorption between 215 and 330 nm is associated with S – → As III charge transfer bands, similar to the transitions observed for the binding of As III by simple mono-, bis-, − or tristhiol-type compounds. While these bands usually appear as smooth or more definite shoulders, in the spectra recorded for the present system, there is a clearcut local absorption maximum slightly below 290 nm.…”

“…While these bands usually appear as smooth or more definite shoulders, in the spectra recorded for the present system, there is a clearcut local absorption maximum slightly below 290 nm. The observed λ max value (= 287 nm) and the intensity of this band (ε 287 nm = 1.91 × 10 3 M –1 cm –1 ) unambiguously reflect three As III -bound thiolates , and are clearly distinct from the less intense transitions characteristic for species with two thiolates. − The trends of the spectroscopic features (Figures and S1) suggest the formation of the same As III –peptide complexes between pH 2.0 and 7.5 and binding of one As III per peptide.…”

“…Nevertheless, as demonstrated by the present example, such bands can be rather prominent in samples of short-length peptides if they are centered in the wavelength regime that do not overlap with the ligand transitions but may also modulate the observed signals at higher energies, i.e., below ∼210 nm. Furthermore, in contrast to the well-defined signs (positive or negative) of the CD signals related to the different secondary structural elements of the peptide backbone, literature data suggests that the LMCT-induced transitions may result in negative or positive signals, depending on the type of ligand, the number/configuration of chirality centers, and their relative positions to the thiolate–metal ion bonds. ,,,, The evolution of the low-energy, CT-related CD bands in the As III - L system at any studied pH (Figures A and S6A,B) and with Hg II at pH 7.5 (Figures B and S6D) provides strong support for the formation of the previously proposed tristhiolate binding mode of L . Indeed, the absence of such features in the Hg II - L sample at pH 2.0 (Figure S6C) is in accord with the higher energy of the LMCT bands in {HgS 2 }-type species, shifting also the related CD signals into the wavelength range of the amide-bond transitions.…”

“…Furthermore, in contrast to the well-defined signs (positive or negative) of the CD signals related to the different secondary structural elements of the peptide backbone, literature data suggests that the LMCT-induced transitions may result in negative or positive signals, depending on the type of ligand, the number/ configuration of chirality centers, and their relative positions to the thiolate−metal ion bonds. 34,41,47,49,64 The evolution of the low-energy, CT-related CD bands in the As III -L system at any studied pH (Figures 4A and S6A,B) and with Hg II at pH 7.5 (Figures 4B and S6D) provides strong support for the formation of the previously proposed tristhiolate binding mode of L. Indeed, the absence of such features in the Hg II -L sample at pH 2.0 (Figure S6C) is in accord with the higher energy of the LMCT bands in {HgS 2 }-type species, shifting Considering the short length of the AfArsR model peptide, we cannot exclude that the CD features below 240−250 nm are also affected by LMCT signatures. In general, the relative intensity of the peptide-related transitions and LMCT contributions to the CD of low-molecular-weight metal complexes is an unresolved and open question.…”

Radiochemistry: A Hot Field with Opportunities for Cool Chemistry

“…Conclusively, controlling and stabilizing As (III) /As (V) coordination complexes represent a veritable, fundamental coordination chemistry challenge. Only a handful of water-stable mononuclear As (III) /As (V) complexes have been reported in the literature, , with electrochemical investigation of ligand effects mostly lacking; this renders prediction of oxidation-mediated decomposition particularly difficult. Organometallic metalloid chemistry can provide inspiration on how to simultaneously stabilize the Lewis acidic and basic character of this ionas demonstrated by O’Halloran and co-workers, transition-metal stabilized systems, where As (III) is exploited for its amphoteric character, can be utilized. , …”