Mechanism of Ag + -Induced Folding of a Bacterial Peptide from Replica-Exchange Molecular Simulations

Interactions between proteins and metal cations are central to biochemical processes and shape protein structures. SilE, an intrinsically disordered protein involved in bacterial silver resistance, folds into α-helices upon binding Ag + ions. Focusing on the B1 peptide fragment from SilE, we investigate the mechanism of Ag + -induced folding with atomistic simulations and experiments. Guided by Mass Spectrometry and NMR, we prepare a structural model of Ag + -bound B1, which we parametrize using DFT. Then, with replica-exchange simulations and deep learning, we map B1’s folding landscape and how it is shaped by Ag + . Specifically, Ag + binding promotes folding by lowering the entropy of the disordered state and stabilizing the folded state. We also describe how Ag + alters the folding pathways. Overall, we improve our understanding of metal-induced protein folding and lay the groundwork for further computational investigations of the bacterial silver-resistance machinery.