Abstract
This dissertation focuses on using rationally designed unnatural peptides to engage cellular membranes, undergo enzyme mediated lipidation, and generate emergent membrane associated assemblies that remodel organelle organization, perturb membrane trafficking, and ultimately control cell fate. Each chapter highlights the design principles and structural optimization of peptide motifs that enable membrane targeting and intracellular transformation, together with mechanistic studies that connect peptide lipidation and self-assembly to specific cellular outcomes. The work describes how membrane interaction can be tuned through molecular structure, how intracellular N-myristoylation can convert peptides into potent bioactive assemblies, and how palmitoylation driven accumulation can nucleate large noncanonical membrane compartments that sequester small GTPases and disrupt trafficking. Through these studies, this dissertation aims to advance supramolecular chemical biology by establishing lipidation enabled peptide assembly as a general strategy to reprogram cellular membranes and to inspire new approaches for probing and modulating complex membrane associated processes.