Date of Award

Spring 5-14-2016

Degree Type


Degree Name

PhD. Chemistry


Chemistry and Biochemistry


Stephen Kelty, Ph.D

Committee Member

Yufeng Wei, Ph.D

Committee Member

Monika Raj, Ph.D

Committee Member

Cecila Marzabadi, Ph.D


Molecular Dynamics, Transmembrane proteins, TRPV1, PIP2, proline mimic, peptide synthesis


Chapter I

The Transient Receptor Potential (TRP) family of ion channels encompasses more than 30 members, which are expressed in many different tissues and cell types.1 Transient Receptor Potential Vanilloid Type 1 (TRPV1) is part of the TRP family gated by vanilloids, heat and protons.2 Molecular modeling will be used in order obtain structural and functional data on TRPV1 in its membrane bound environment. In particular, the transmembrane and C-terminal domain regions of TRPV1 are of particular interest. The S1-S4 region of the channel is the putative ligand-binding segment, while the C-terminal domain is suggested to respond to temperature and is regulated by phosphotidylinosides (PIP2). Despite the crucial roles in mediating signal transductions at both peripheral and central nervous systems, TRP channels are poorly understood in the context of structures and mechanisms.4 A molecular model of the published transmembrane section of TRPV1 along with the putative, unstructured C-terminal domain was created using their respective homology models and inserted into their membranes.5 Simulations were performed using both a lipid membrane containing PIP2 and one without PIP2 in order to determine its role in TRPV1 activation/deactivation. Molecular dynamics simulations could provide pivotal information about ligand binding, voltage sensing, interaction with heat/cold and proton binding for TRPV1. MD simulations alluded to the fact that when both temperature and PIP2 are present a greater degree of conformational change is observed. A greater understanding of the structure of TRPV1 could provide important details on how to alleviate certain diseases such as pain, asthma and diabetes.

Chapter II

Proline is unlike any other natural amino acid; it is the only amino acid that contains a pyrrolidine ring structure and is a secondary amine.56 Pseudoproline was derived in order to address the solubility and aggregation difficulties that can arise when performing FMOC solid phase synthesis of peptides.60 The presence of pseudoproline in a peptide overcomes aggregation by disrupting helices and β-sheets; leading causes in peptide aggregation.60 Derived from serine, cysteine or threonine via cyclo-condensation reaction with aldehydes or ketones, pseudoproline is commercially available, however, it undergo peptide synthesis through SPPS. A new proline mimic be utilized by SPPS; additionally, it is hypothesized to also decrease aggregation and increase solubility. The proposed mechanism for the proline mimic increased stability is due to a hypothesized formation of stable β hairpin turn during peptide synthesis. Density functional theory (DFT) calculations were performed in order to determine the equilibrium constant (K) and total energy of peptides containing proline, pseudoproline or the proline mimic. Molecular dynamic simulations were used in order to generate theoretical Ramachandran plots, which provided essential insight into the secondary structure of all three peptides.