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 antimicrobial agents. They have been employed in medical applications for centuries. It is also known that some bacteria can resist to silver(I) treatments through an efflux mechanism. However, the exact mechanism of action remains unclear. 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 is, however, still an open question. Here, we demonstrate that the standard 12-6 Lennard-Jones parameters (previously developed to describe the hydration free energy with the TIP3P water model) significantly underestimate the interaction strength between silver(I) and both methionine and histidine. These are two key amino-acid residues in silver(I)-binding motifs of proteins involved in the efflux process. Using free-energy calculations, we calibrated non-bonded fix (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 -helical content of the LP1 oligopeptide, in agreement with previously reported Circular Dichroism (CD) experiments. Future improvements are outlined. The implementation of these new parameters is straightforward in all simulation packages that can use the CHARMM36m force field. It sets the stage for the modeling community to study more complex silver(I)-binding processes such as the interaction with silver(I)-binding-transporter proteins.