We report a quantum-mechanical study aimed at elucidating connections between lead coordination and toxicity. In agreement with experimental data, lead binds to cysteine-rich sites and introduces new coordination preferences that do not stabilize the proper form of zinc-binding domains. Electronic structure calculations and orbital analysis reveal that the classical role of stereochemically active lone-pair orbital might be simplistic. The optimal ligand arrangement is modulated by s-p orbital mixing and stabilization of lone-pair orbital, which is differently influenced by S- and N-donor atoms. Computed structural parameters agree with crystallographic data. Computed UV spectra identifies characteristic bands for lead poisoned peptides at 260 and 330 nm, assigned as ligand-to-metal charge-transfer bands. Comparison of computed spectra with model peptides suggests 4- and 3-coordinated lead domains coexisting in the poisoned protein environment.

We conclude that sensitive structural and dynamic probes such as resonance Raman (RR) spectroscopy guided by calculations could become an essential tool for understanding lead poisoning mechanisms. Simulations of RR spectra of cysteine-rich lead domains indicate that a specific structure and coordination mode of lead might be detectable by RR spectroscopy. We predict that when the excitation wavelength is in resonance with UV lead bands, the enhancement of vibrational modes is found for Pb-S stretching and bending modes and also for characteristic C-S stretching and CH2 bending modes of cysteine. More importantly, computed RR intensities for lead domains show unique patterns and might be successfully applied to identify and/or monitor structure and coordination of lead in poisoned proteins.