Debe, Derek A. (2001) Shaving levinthal with Occam's Razor : Understanding the rate limiting step in protein folding. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:11122009-154318044
How do proteins fold? This thesis addresses this simple yet important question by developing a first principles theoretical framework that accurately describes the experimentally observed protein folding rate data. The success of the new theory suggests that single domain proteins fold according two a two- state mechanism consisting of (i) a random, diffusive search for the native topology, followed by (ii) non-random, local conformation changes within the native topology to find the unique native state. In chapter 1, a popular analogy between protein folding and the game of golf is used to qualitatively illustrate the most important aspects of the new theory. In chapter 2, mean-field computational methods are developed that allow the time involved in the rate limiting diffusive search for the native state to be calculated. Chapters 3 and 4 remove the mean-field restriction from the methods of chapter 2, allowing the folding rate for an arbitrary two-state folding protein to be calculated. Chapter 5 then explores how real proteins deviate from this ideal model by examining the roles that non-random mechanisms such as helix, hydrophobic core, and 13-turn formation play in the early folding process. Finally, chapter 6 develops an empirical model that also capably predicts protein folding rates, adding further support to the proposed folding mechanism.
|Item Type:||Thesis (Dissertation (Ph.D.))|
|Degree Grantor:||California Institute of Technology|
|Division:||Chemistry and Chemical Engineering|
|Awards:||The Herbert Newby McCoy Award, 2001|
|Thesis Availability:||Restricted to Caltech community only|
|Defense Date:||6 April 2001|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||17 Nov 2009 22:02|
|Last Modified:||26 Dec 2012 03:18|
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