Analysis of the thermodynamic determinants of protein fold specificity in the denatured state ensemble

Although the thermodynamic control of protein folding has been known for decades, a complete understanding of the thermodynamic determinants that defining protein folds is still elusive. In this regard, it is becoming clear that focusing only on the native states of protein folds will be insufficient for deciphering the protein folding problem. Knowledge of the thermodynamics of the denatured state is also necessary. In this project, the thermodynamic determinants of the native fold, present in the denatured ensemble, were investigated and the critical role of the denatured state ensemble in controlling protein folding is discussed. In this work, the COREX algorithm, used until now to model the native state ensemble, was for the first time used to model the denatured state ensembles and investigate the relationship between denatured ensemble energetics and sequences, as well as between denatured ensemble energetics and secondary structures. Substantial thermodynamic differences were found between the denatured and the native states ensembles. The generality and robustness of our results were validated by performing fold-recognition experiments that matched sequences with their respective folds using only energetic information. The success of our study and the unique energetic information found in denatured states suggest a wide range of strategies for developing novel algorithms for protein prediction and classification. \r\nIn addition, this work has particular medical relevance. Understanding the chemical and physical processes underlying thermodynamic determinants of protein folding specificity will enable the rational design of drugs to combat the rapidly expanding family of misfolding diseases. Some misfolding diseases are known to be related to non-specific beta sheet formation. The value of this project lies in the detailed analysis between denatured ensemble energetics and sequences, as well as between energetics and secondary structures. Correlation analysis between structure and energetic information revealed that denatured states have evolutionarily evolved to avoid early beta sheet formation, suggesting that the therapeutic strategies to combat misfolding diseases (especially for diseases related to non beta sheet formations) could be found in the energetics information of the denatured states rather than the native states. \r\n

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor

The University of Texas Medical Branch

Year dc:date.issued

2008

Author dc:creator

• Suwei Wang

Advisor dc:contributor.advisor

• Robert O. Fox

Committee members dc:contributor.committeemember

• Vincent Hilser
• R. Bryan Sutton
• Bernard M. Pettitt
• Andres F. Oberhauser

• thermodynamic determinants
• protein fold
• denatured states

Statement dc:rights

• Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.

Language dc:language.iso

eng

Dc Identifier Other

etd-06202008-144751

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/122