Enhanced Sampling Approaches to Investigate Drug Transport in AdeC

Ade-ABC is a key bacterial efflux pump system, facilitating the transport of antibiotics and other small molecules across the outer membrane of Gram-negative bacteria. Understanding the drug passage mechanism through Ade-ABC is essential for developing novel strategies to counteract bacterial resistance. We have recently modeled drug passage through TolC, a protein related to AdeC, using a cruder approach called steered molecular dynamics [1]. This method provides qualitative information but more quantitative data on the thermodynamical and kinetic parameters of the passage process is required for drug design purposes.
In this project, enhanced sampling techniques, such as metadynamics and umbrella sampling, will be employed to explore the conformational changes and energy barriers associated with antibiotic translocation through the AdeC component of the Ade-ABC channel. The enhanced sampling methods will allow us to sample rare events and explore free energy surfaces that are difficult to access using all atom molecular dynamics simulations. The focus will be on characterizing the key transition states and potential energy profiles that govern the drug passage process. This study aims to provide detailed insights into the drug transport mechanism of AdeC, contributing to the broader understanding of bacterial resistance mechanisms and offering potential strategies for targeting efflux systems.
Through this project, students will gain hands-on experience in enhanced sampling algorithms, analyzing protein-drug interactions, and interpreting large-scale protein dynamics by writing codes in Tcl and Python. Students will also develop skills in handling high-performance computing environments and scientific communication, equipping them for future research in computational biophysics and drug discovery efforts.
The aim of this project is the application of enhanced sampling techniques to study the drug passage mechanism through an efflux channel. The focus is on using these techniques to capture rare events and map the free energy landscape, which allows for a detailed examination of the conformational changes and energy barriers involved in the drug translocation process. This design enables the exploration of molecular mechanisms that are challenging to observe through standard simulations.
References:
[1] I. Kantarcioglu, I. Gaszek, T.F. Guclu, M.S. Yildiz, A.R. Atilgan, E. Toprak, C. Atilgan, "Structural Shifts in TolC Facilitate Efflux-Mediated β-lactam Resistance," Communications Biology; 7, 1051 (2024). [link]