Potent Cyclic Tetrapeptide for Lead Detoxification.

Lead (Pb) is a ubiquitous poisonous metal, affecting the health of vast populations worldwide. Medications to treat Pb poisoning suffer from various limitations and are often toxic owing to insufficient metal selectivity. Here, we report a cyclic tetrapeptide that selectively binds Pb and eradicates its toxic effect on the cellular level, with superior potency than state-of-the-art drugs. The Pb-peptide complex is remarkably strong and was characterized experimentally and computationally. Accompanied by the lack of toxicity and enhanced stability of this peptide, these qualities indicate its merit as a potential remedy for Pb poisoning.

Mapping Conformational Space of All 8000 Tripeptides by Quantum Chemical Methods: What Strain Is Affordable within Folded Protein Chains?

To gain more insight into the physicochemical aspects of a protein structure from the first principles, conformational space of all 8000 "capped" tripeptides (i.e., N-Ac-X1X2X3-NH-CH3, where Xi is one of the 20 natural amino acids) was investigated computationally. An enormous dataset (denoted P-CONF_1.6M and containing close to 1 600 000 conformers in total) has been obtained by employing a composite protocol combining density functional theory, semiempirical quantum mechanics (SQM), and state-of-the-art solvation methods with 1000 K molecular dynamics (MD) used to generate initial structures (200 snapshots for each tripeptide). This allowed us to present the first rigorous QM-based glimpse at the vast conformational space spanned by small protein fragments. The same computational procedure was repeated for tripeptide fragments taken from the SCOPe database of three-dimensional protein folds, by restraining them to their geometry in a protein. Such complementary data allowed us to compare the distribution of conformational strain energies of unrestrained tripeptidic fragments "in solvent" with those in existing protein chains. Besides providing a rigorous (ab initio) proof of a few well-known concepts and hypotheses concerning protein structures, such as the distribution of (φ, ψ) angles in Ramachandran plots, we have made several observations that came as a certain surprise: (1) distribution of conformational energies does not significantly differ between the "unbiased/unrestrained" conformers obtained from MD sampling in solvent and the biased conformers, i.e., those of a given tripeptide obtained from protein structures; (2) conformational (strain) energy window up to ∼20 to 25 kcal·mol-1 is readily available to tripeptide fragments within the context of a protein chain; (3) overpopulation in certain regions of Ramachandran plot was observed for the unbiased conformers. Last but not least, the massive dataset of accurate (DFT-D3//COSMO-RS) conformational (free) energies of ∼1.6 M peptide conformers, P-CONF_1.6M, obtained throughout this work may serve as excellent dataset for calibrating and benchmarking of popular force fields.