Energetics of [alpha]-helix formation in peptides and proteins

This thesis focuses on the energetics of !-helix formation in peptides and proteins. The [alpha]-helix is the most prevalent type of secondary structure found in proteins, and has arguably dominated our thinking about protein structure since its discovery, as it plays an important role in the early stages of protein folding. The intrinsic helical propensities of the natural amino acids make a very important contribution to secondary structure formation during these earliest folding events of peptides and proteins, whether studied in isolation in vitro, or during the co-translational folding of the nascent polypeptide chain during protein biogenesis in vivo. The energetics of helical propensities have been studied intensively over the last four decades in both peptides and proteins, but fundamental controversies remain to date, as essential experimental parameters, such as temperature or pH, have largely been ignored in the past. A new approach is needed that yields a revised helical propensity scale for the natural amino acids, if these intrinsic properties are to be incorporated and used in algorithms that predict peptide and protein structure and stability in applications of molecular modeling, protein engineering and design, or medicinal chemistry. In this thesis, context- and temperature-dependences of the helical propensities are explicitly explored both in optimized peptide and protein models, and a revised scale of intrinsic helical propensities is derived. The groundwork for helical propensity assignments in a peptide model is laid by rigorous characterization of spaced, solubilized polyalanine peptides as the ideal host to study intrinsic helical propensities in a solvent-exposed, context-free model.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2009

Author dc:creator

• Schubert, Christian Reinhold

Advisor dc:contributor.advisor

• Daniel S. Kemp.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/49551

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/49551