Integrating Molecular Dynamics and Deep Learning to Elucidate Conformational Plasticity Underlying the Reduced...

The escalating crisis of multidrug-resistant bacteria demands a new generation of antibiotics. Glycocin F (GccF), a potent bacteriocin, is a promising candidate, but its function hinges on unique post-translational glycosylation. Intriguingly, a seemingly minor chemical tweak of α-methylation at Ser18 of GccF destroys its activity, reducing its potency by 1000-fold. To quantify how this subtle chemical change leads to profound functional compromise, we used an advanced molecular dynamics framework guided by Variational Autoencoder to unravel GccF's complex dynamics. Our findings reveal that native glycosylation preserves conformational plasticity to maintain functionally relevant conformations. In stark contrast, α-methylation introduces local rigidity, locking the peptide into fewer metastable basins with significantly slower transition rates. This leads to the disruptions of the α-helix structure, which perturbs the loop-helix coupling and traps the peptide into nonfunctional conformations. Together, these findings demonstrate how a subtle modification can dictate a peptide's function by profoundly altering its structural dynamics.