Pseudomonas aeruginosa Outer Membrane Protein Modeling
T.P. Straatsma, Principal Investigator
Funding Agency: National Institutes of Health, National Institute of Allergy and Infectious Diseases
The Pseudomonas aeruginosa Outer Membrane Protein Modeling project team at Pacific Northwest National Laboratory (PNNL) is developing and applying new molecular modeling and simulation capabilities for the study of outer membrane proteins of P. aeruginosa and Escherichia coli in realistic, atomic-detail models of the lipopolysaccharide (LPS) membrane. Novel computational methods and tools are used to provide a molecular level characterization of the specific interactions that determine the structure, integrity, dynamics and thermodynamics of the lipopolysaccharide outer membrane of P. aeruginosa, and to contribute to the understanding of the effect of these membranes on small molecule binding, transmembrane protein stability and signal and material transport across these membranes through channel proteins and porins. Molecular modeling and molecular dynamics computer simulations are well suited to study these specific molecular interactions by comparative analysis of electrostatic signatures, and energetic and dynamic properties of molecular models for outer microbial membranes.
Our focus is on the outer membrane of P. aeruginosa, one of the most important opportunistic human pathogens, in comparison with the outer membrane of Escherichia coli, in order to determine the role of elements that are specifically found in the LPS structure of the outer membrane of P. aeruginosa in presenting an exceptionally effective barrier to many hydrophobic compounds, including many antibiotics. Other systems for intrinsic antibiotic resistance are multi-drug efflux systems in the outer membrane, such as the MexAB-OprM RND efflux system, that excrete antimicrobial agents that have entered the periplasm through the non-specific porins. The tools and procedures that will be developed as part of this work will be applicable to the study of outer membranes of any Gram-negative microbial outer membrane, including other microbes of interest in our laboratory such as Salmonella typhimurium and Shewanella oneidensis, an aquatic organism similar to Vibrio cholerae.
This work builds on our Laboratory's strong expertise in developing molecular modeling applications and the unique experience in applying these capabilities for the simulation of LPS membranes and outer membrane proteins of Gram-negative bacteria using realistic atomic models.
