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Shaving levinthal with Occam's Razor : Understanding the rate limiting step in protein folding

Citation

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. http://resolver.caltech.edu/CaltechTHESIS:11122009-154318044

Abstract

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:Restricted to Caltech community only
Research Advisor(s):
  • Goddard, William A., III (advisor)
  • Chan, Sunney I. (co-advisor)
Thesis Committee:
  • Dougherty, Dennis A.
  • Gray, Harry B.
  • Rees, Douglas C.
Defense Date:6 April 2001
Record Number:CaltechTHESIS:11122009-154318044
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:11122009-154318044
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5372
Collection:CaltechTHESIS
Deposited By: Tony Diaz
Deposited On:17 Nov 2009 22:02
Last Modified:28 Jul 2014 17:48

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