Modelling the interaction between silver(I) ion and proteins with the 12-6 Lennard-Jones potential: a bottom-up parameterization approach

Silver(I) ions and organometallic complexes thereof are well established antimicrobic agents. They have been used in medical applications for many centuries. It is also known that some bacteria can resist to silver(I) treatments by means of an efflux mechanism guided by a set of silver-binding transport proteins (e.g., SilE/F) and transmembrane channel. The exact mechanism of action, however, is not fully clear yet. All-atom force-field simulations can provide valuable structural and thermodynamic insights on the molecular processes of the underlying mechanism. Lennard-Jones parameters of silver(I) have been available for quite some time; their applicability to describe properly the binding properties (affinity, binding distance) between silver(I) and peptide-based binding motifs remains, however, an open question. We show here that the standard 12-6 Lennard-Jones parameters (previously developed to describe the hydration free energy with the TIP3P water model) drastically underestimate the strength of interaction between silver(I) and methionine as well as histidine. These are two key residues of the silver(I)-binding motifs in the transport proteins SilE/F. Using free-energy calculations, we calibrated NBFIX parameters for the CHARMM36m force field to reproduce the experimental binding constant between amino acid sidechain fragments and silver(I) ions. We then successfully validated the new parameters on a set of small silver-binding peptides with experimentally known binding constants. In addition, we could monitor how silver(I) ions increase the alpha-helical content of the LP1 oligopeptide, in agreement with previously reported Circular Dichroism (CD) experiments. Future improvements are outlined. The integration of these new parameters is straightforward for most simulation packages. It sets the stage for the modeling community to study more complex silver(I)-binding processes such as with the transporter proteins SilE/F