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 is an intrinsically disordered protein which binds Ag+ ions as part of a bacterial resistance mechanism against silver toxicity. The structural consequences of silver binding to proteins are still unclear. Here, focusing on the B1 peptide from SilE, we investigate the mechanism of Ag+-induced peptide folding using molecular simulations, NMR, and deep learning. First, we parametrize Ag+-protein interactions using DFT. Then, we use replica-exchange simulations, deep learning and NMR to map B1’s folding landscape and reveal how it is shaped by Ag+. Our results recapitulate B1’s experimentally-observed propensity to fold into an alpha-helix upon Ag+-binding. Ag+-binding promotes N-ter-initiated folding by entropic penalization of the disordered state and electrostatic stabilization of the folded state. Overall, we improve the understanding of metal-induced protein folding, and provide insights into bacterial silver-resistance and towards design of Ag+-controlled foldable peptides.