Antibiotics have significantly improved human health around the globe. However, evolution has increased antibiotic resistance among bacteria, creating a critical public health concern. Thus, it is important to understand antibiotic resistance mechanisms in bacteria. Members of the small multidrug resistance (SMR) protein family confer resistance to antibiotics by leveraging an established proton gradient, which couples to glutamate residues within the interior of the transporter. SMR proteins are small homodimers and are broadly classified into Qac and Gdx sub-families based on selective substrate transport across the membrane. Using molecular dynamics (MD) simulations, three different EmrE structures and one Gdx-Clo structure from the Qac and Gdx sub-families respectively are assessed to evaluate the similarities and differences at the molecular scale. To evaluate the impact of glutamate protonation, four possible protonation states for both EmrE and Gdx-Clo are compared to examine the structural and potentially functional changes. Root-mean square deviation analysis suggests Gdx-Clo has lower root-mean square deviation compared to EmrE for all different protonation states by approximately 2 Å. Even in the absence of substrate, the number of water molecules within the lumen is greater for EmrE than it is for Gdx-Clo. The larger EmrE lumen with greater flexibility is consistent with EmrE accepting large cationic substrates such as tetraphenylphosphonium, while the more rigid Gdx-Clo favors smaller cations such as guanidinium. These results help understand the selective substrate transport in SMR transporters.

Structural principles governing substrate selectivity in small multidrug resistance proteins

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