Alexandria Digital Research Library

Design strategies for peptide amphiphile micelles

Author:
Marullo, Rachel
Degree Grantor:
University of California, Santa Barbara.Chemical Engineering
Degree Supervisor:
Tirrell Matthew
Place of Publication:
[Santa Barbara, Calif.]
Publisher:
University of California, Santa Barbara
Creation Date:
2011
Issued Date:
2011
Topics:
Chemical engineering
Description:

Peptide amphiphiles (PAs) are capable of self-assembly into micelles which can be used in the targeted delivery of peptide therapeutics and diagnostics. PA micelles exhibit a structural resemblance to proteins, having folded bioactive peptides displayed on the exterior of a hydrophobic core. However, PA self-assembly is often unpredictable and design insight is needed to control the properties of PA micelles from the bottom up. In this regard, we have studied several design factors.

Peptide length was systematically varied using a heptad repeat PA to study headgroup secondary structure. For all PAs the addition of a C12 tail induced micellization and secondary structure. PAs with 9 amino acids formed beta-sheet interactions upon aggregation, whereas the 23 and 30 residue peptides were displayed in an alpha-helical conformation. The 16 amino acid PA experienced a structural transition from helix tosheet, indicating that kinetics play a role in secondary structure formation.

A DNA binding "bZip" PA derived from the GCN4 protein was used as a model peptide to explore the relationship between self-assembly and activity. Micellization induced secondary structure and stabilized a native-like binding orientation, however, the PAs had a strong affinity for all DNA sequences and were not able to recognize the specific target sequence of GCN4.

Because of the propensity of PAs to form cylindrical micelles, their use is limited in applications where small spherical micelles are desired. We developed a platform method for controlling the self-assembly of biofunctional PAs into spherical 50 nm particles using dendrimers as shape-directing scaffolds. This templating approach resulted in biocompatible, stable protein-like assemblies displaying peptides with native secondary structure and biofunctionality.

The final property studied was micelle stability. Studies of two bZip peptide sequences with di-C16 tails showed that a short 7 amino acid coiled-coil nucleation sequence imparted a significant amount of stability to the micelles, leading to an order of magnitude decrease in the dissociation rate. A bZip peptide with a palmitic acid tail had the same CMC and dissociation kinetics as with a fluorodecanoic acid tail, indicating that short fluorocarbon tails can be investigated in PA design over longer hydrocarbon tails.

Format:
Text
Collection(s):
UCSB electronic theses and dissertations
ARK:
ark:/13030/m5959j6m
Merritt ARK:
ark:/13030/m5959j6m
Rights:
Inc.icon only.dark In Copyright
Access: This item is restricted to on-campus access only. Please check our FAQs or contact UCSB Library staff if you need additional assistance.