Date of Graduation

5-2025

Document Type

Thesis

Degree Name

Master of Science in Chemistry (MS)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

Moradi, Mahmoud

Committee Member

Fan, Chenguang

Second Committee Member

Adams, Paul D.

Keywords

cholesterol; drug delivery design; therapeutic applications

Abstract

The multidrug resistance-associated protein 1 (MRP1/ABCC1) is an ATP-binding cassette (ABC) transporter that mediates the cellular efflux of endogenous and xenobiotic substrates, including therapeutic drugs. Its overexpression is a major contributor to multidrug resistance in cancer, which tends to result in negative clinical results. Even with considerable progress made in structural biology, the intricate details of how membrane lipid composition affects the conformational changes and functional switches of MRP1 still lack explanation.

This thesis employs long-timescale, all-atom molecular dynamics (MD) simulations to study the influence of various lipids on MRP1 lipid bilayer environments. Both inward-facing and outward-facing conformations of MRP1 were simulated using physiologically relevant POPC and POPE bilayers containing cholesterol. Attention was directed to key structural features, including domain movements, RMSD stability, salt bridge persistence, and hydrogen bonds.

The results demonstrate that bilayer composition strongly impacts the structural flexibility of MRP1. POPE-rich and cholesterol-containing bilayers have been demonstrated to strengthen stabilizing, electrostatic, and nucleotide-binding domain (NBD) compaction, such as ASP1453–LYS1332 and GLU1064–LYS1343, particularly in the inward-facing state. Conversely, POPC-rich membranes exhibit greater freedom of movement and weaker electrostatic interactions. In the post-hydrolysis outward-facing state, cholesterol destabilizes NBD by salt bridge severing and increasing inter-NBD distance, which aligns with reset-ready conformation. A salt bridge ASP749 and ARG1327 was found to undergo dissociation post ATP hydrolysis in all systems, acting as a structural switch onto the NBD opening.

These changes highlight the dynamic nature of the lateral pressure profile that the lipid environment exerts as an allosteric switch on MRP1 function. The results elucidate how specific lipids and membrane components dictate the function of the transporter, thus allowing for targeted approaches to modulate ABC transporter activity through membrane lipid manipulation. Such approaches may aid in formulating new therapeutic strategies to combat drug resistance in cancer and other diseases associated with proliferative ABC transporters.

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