Semester

Spring

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Fabien Goulay

Committee Co-Chair

Blake Mertz

Committee Member

Brian Popp

Committee Member

Stephen Valentine

Committee Member

Kenneth Ryan

Abstract

Cancer is a leading cause of death in the world today. Current methods of treatment fail to distinguish the difference between cancer cells and cells of healthy tissue, leading to off-target effects, often with terminal outcomes. A potential solution to this challenge is to target the cancer cells’ microenvironment. One universal characteristic across all cancer cells is the acidic extracellular environment. The pH-Low Insertion Peptide (pHLIP) is a membrane-active peptide with acid-sensitive function, undergoing folding and insertion into a transmembrane alpha-helix. pHLIP is a promising candidate to be used to deliver anti-cancer agents exclusively to cancer cells. Although the mechanism for pHLIP is well-characterized, the detailed pathway of pHLIP function remains poorly understood. Using umbrella sampling (US) simulations, we mapped out the transition of pHLIP between all three states (I unfolded and solvated; II: unfolded and bound to the membrane surface; III: folded and inserted into the membrane). We found that it is necessary to quantify the behavior of pHLIP as an independent function of both the N-terminal and C-terminal halves of the peptide, consistent with biophysical studies that have identified unique a complex relationship between residue titration, bilayer hydration, and insertion of pHLIP.

It is possible to design membrane-active peptides with acid-sensitive properties similar to pHLIP with the use of hydrophobicity scales. One scale in particular, the Wimley-White scale, was developed using a level of detail that accounts for energy contributions from the backbone and side chains of each amino acid. This scale has limited applicability in model membrane systems as it fails to account for electrostatic contributions between residues and charged lipids. In this work, we use molecular dynamics to model the membrane partitioning of several hydrophobic residues. Our preliminary results show validation of the Wimley-White scale with atomistic detail. This provides us with the groundwork to explore the effects of electrostatic interaction in model lipid bilayers.

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