Understanding the structure and function of the Dcap channel from acinetobacter baumannii using MD simulations

Abstract

DcaP is putative dicarboxylate specific channel, located in the outer membrane of the pathogen Acinetobacter baumannii. The X-ray crystal structure reveals that DcaP is the first trimeric channel identified in Acinetobacter baumannii and could play an important role in substrate and antibiotic permeation. To characterize the permeation properties of this channel, we have carried out the applied field MD simulations in the presence of ions (KCl), substrates (phthalic acid, succinic acid) and a β-lactam antibiotic (sulbactam). Additionally, free energy calculation have been carried out using metadynamics simulations to identify the lowest energy permeation path along the 2D free energy surfaces and the most prominent residues during translocation. These simulations clearly suggest that the DcaP channel is involved in the permeation of these solutes and results are complemented with electrophysiology experiments. Furthermore, the crystal structure reveals that DcaP have an extended N-terminus domain in the periplasmic space, which is presumably known to form the coiled-coil structure (uniprot entry: A0A0B9X9I7). As the N-terminus domain was not resolved in the crystal structure, we have predicted the structure using an extensive modeling approach. Moreover, the simulations and electrophysiology experiments suggest that the N-terminus might play an important role in the formation of a stable trimer. Overall, we have built the so far unknown structure-function relationship for the DcaP channel which could help in designing next generation antibiotics efficiently permeating through this channel.