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

Author: Debe, Derek Anthony

Year: 2001

Degree: Dissertation (Ph.D.)

Advisors: Chan, Sunney I.; Goddard, William A., III

Committee Members: Rees, Douglas C.; Dougherty, Dennis A.; Gray, Harry B.; Chan, Sunney I.; Goddard, William A., III

Option: Chemistry

DOI: 10.7907/p4yc-y834

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.

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