Insight into uranyl binding by cyclic peptides from molecular dynamics and density functional theory

It is a challenging task to develop uranyl-chelating agents based on peptide chemistry. A recently developed cationic dummy atom model of uranyl in conjunction with the classical molecular dynamics simulation presents a helpful utility to study the chelation of uranyl by peptides with a low computational cost. In the present study, it was used to describe the chelation of uranyl by the cyclic decapeptide with 4 Glu residues cycGluArgGluProGlyGluTrpGluProGly and its derivatives containing two phosphorylated serines in place of two Glu, termed pS16, pS18, pS38, and pS68. The obtained structures were further studied by density functional theory (DFT) and subsequent density analysis. We show that a combination of steered molecular dynamics and simulated annealing, using standard forcefields for peptide with the cationic dummy atom model of uranyl, can quickly and reliably obtain binding modes of uranyl-peptide complexes. Classical molecular dynamics simulation in explicit water produces geometry very close to the DFT-optimized structure. The presence of uranyl completely changes the conformation of these cyclic peptides from unstructured to organised. The simulation of a peptide with two uranyl units explained why only the 1:1 ratio of peptide and chelated-uranyl is observed experimentally in most cases, by the insufficiency of the anionic residues for the chelation of two UO 2 2 + units, but that pS16 can accommodate two such units.