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Dissertation
Defining local order in the unfolded state using short peptide model systems and spectroscopic methods: conformational biases, mediation by solvation, and nearest neighbor effects!
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2014
DOI:
https://doi.org/10.17918/etd-6056
Abstract
This thesis describes conformational ensembles of amino acid residues in unfolded peptides, and how their dependence on solvation and nearest-neighbor interactions can be obtained by a combination of vibrational and NMR spectroscopies. To this end, short peptide model systems may be chosen ranging from dipeptides to blocked and unblocked tripeptides. The question then arises whether one type of model system is more suitable for studying conformational propensities. Results from our spectroscopic studies suggest that the conformational ensemble of trialanine and its high pPII content are independent of the peptide's protonation state. In addition, we find that the conformational ensemble of the alanine dipeptide, a classic peptide model system, resembles the unblocked GAG model peptide, as expected in the absence of any end effects. To explore the physical basis underlying residue-level conformational bias we utilized UVCD and NMR derived 3J coupling constants to decompose the Gibbs free energy landscape. We found that the thermodynamics underling conformational propensities of (1) trialanine in different binary solvents and (2) GxG peptides in water exhibit a near exact enthalpy-entropy compensation involving rarely observed isoequilibria. Their existence indicates peptide solvation as the common physical mechanism behind conformational preferences. Contrary to the isolated pair hypothesis, an ingredient of the classical random coil model, amino acid residues can not be considered as isolated from their neighbors in the unfolded state. To explore nearest neighbor (NN) interactions, we chose a series of "GxyG" host guest peptides, where x/y={A,K,LV}. Utilizing a six different NMR J- coupling constants in conjunction with amide I' (IR, VCD, Raman) band profiles we extracted the conformational distributions of x and y residues in the GxyG peptides. Our data reveal large changes in conformational distributions due to neighbor interactions, contrary to the isolated pair hypothesis. Interestingly, residues that have large intrinsic biases towards specific sub-populations tend to loose these preferences upon interaction with a given neighbor, indicating a degree of conformational randomization. Strong effects induced by residues with bulky side chains suggests that the underlying mechanism is the the disruption of neighboring residues' hydration shells.
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Details
- Title
- Defining local order in the unfolded state using short peptide model systems and spectroscopic methods
- Creators
- Siobhan Eileen Toal - DU
- Contributors
- Reinhard Schweitzer-Stenner (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Other Identifier
- 6056; 991014632160404721