Semester

Fall

Date of Graduation

2021

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

John Blake Mertz

Committee Member

Brian Popp

Committee Member

Justin Legleiter

Committee Member

Jonathan Boyd

Committee Member

Valery Khramtsov

Abstract

Cancer is the second leading cause of death in the US with over 1.7 million new cases each year. Current cancer treatments tend to also target healthy tissues due to similarities with cancerous ones, resulting in acute side effects. Early detection is the best approach towards defeating cancer, however, modern imaging techniques require sizeable samples, often implying a late stage in the disease. One common attribute of tumors is their acidic microenvironment, which can be taken advantage of.

The pH Low Insertion Peptide (pHLIP) is a membrane-active peptide that can take advantage of the acidic microenvironment surrounding cancer cells. pHLIP can spontaneously fold and insert unidirectionally as a transmembrane into lipid membranes under acidic conditions. Thus, pHLIP is able to transport drugs across cancerous membranes and deliver it to the interior of the cell. Although the mechanism of insertion and exit of the peptide has been thoroughly studied through experimental and computational approaches, there are still elements of the peptide and its behavior that are not fully understood.

This dissertation focuses on all-atoms molecular dynamics (MD) simulations to study the interactions between pHLIP and its environmental factors. Through High Performance Computing (HPC) at West Virginia University (WVU), we were able to map the initial stages of exit of pHLIP, determine the effect of peptide insertion on the dynamics of a complex lipid bilayer and provide new insights into the environmental factors affecting pHLIP in solution. The results reported in this dissertation will aid the future development of pHLIP-based early detection and targeting agents.

Embargo Reason

Publication Pending

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