Active Site Plasticity of the Bacterial Sliding Clamp

The rise of antibiotic resistance poses a severe global threat, specifically due to the emergence of multiresistant bacteria (ESKAPE pathogens), which are responsible for countless deaths globally. Consequently, the development of novel antibiotics is in dire need. Targeting proteins essential to DNA replication is a promising pathway, making the β-sliding clamp (β-SC) an attractive target. Currently, there are no antibiotics on the market that target the β-SC. However, numerous compounds are being investigated to create an antibiotic with high potency against a broad range of bacterial species. Interestingly, most proposed compounds do not bind to the entire active site, which may reduce their potential as high-potency inhibitors. This is due to the active site residue Met at position 362, adopting a "closed" conformation, preventing inhibitors access into Subsite II of the active site. This study explored the effect of key residues on the plasticity of the β-SC active site using molecular dynamics and metadynamics simulations under different physiological states. Our results show that the Met gate exhibits flexibility and both open and closed states are thermodynamically and kinetically accessible.