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Shaving Levinthal with Occam's Razor: Understanding the Rate Limiting Step in Protein Folding


Debe, Derek Anthony (2001) Shaving Levinthal with Occam's Razor: Understanding the Rate Limiting Step in Protein Folding. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/p4yc-y834.


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.))
Subject Keywords:Chemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:The Herbert Newby McCoy Award, 2001
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Chan, Sunney I. (advisor)
  • Goddard, William A., III (co-advisor)
Thesis Committee:
  • Rees, Douglas C. (chair)
  • Dougherty, Dennis A.
  • Gray, Harry B.
  • Chan, Sunney I.
  • Goddard, William A., III
Defense Date:6 April 2001
Record Number:CaltechTHESIS:11122009-154318044
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5372
Deposited By: Tony Diaz
Deposited On:17 Nov 2009 22:02
Last Modified:09 Feb 2023 23:55

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