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The early events of protein folding : Simulations of polyalanine folding into an alpha-helix


Bertsch, Ruth Ann (1998) The early events of protein folding : Simulations of polyalanine folding into an alpha-helix. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/vewx-3f78.


The kinetics of α-helix formation in polyalanine and polyglycine eicosamers (20-mers) were examined using the Newton-Euler Inverse Mass Operator (NEIMO) method (Jain et al. (1993) J. Comp. Phys. 106: 258-268), a new type of torsional coordinate molecular dynamics (MD). One hundred fifty-five (155) different MD experiments were carried out on extended (Ala)_(20) under identical conditions for 0.5 ns each, and 129 of the simulations (83%) formed a persistent α-helix. In contrast, the extended state of (Gly)_(20) only formed a right-handed α-helix in two of the 20 MD experiments (10%), and these helices were not as long or as persistent as those of polyalanine. This is consistent with the helix propensities of the natural amino acids. The analysis of all 155 simulations show helix formation to be a competition between the rates of (a) forming local hydrogen bonds (i.e., hydrogen bonds between any residue i and its i + 2, i + 3, i + 4, or i + 5th neighbor) and (b) forming nonlocal hydrogen bonds (HBs) between residues widely separated in sequence. Local HBs grow rapidly into an α-helix; but, nonlocal HBs usually retard helix formation by "trapping" the polymer in irregular, "balled-up" structures. Most trajectories formed some nonlocal HBs, sometimes as many as eight. But, for (Ala)_(20), most of these eventually rearranged to form local HBs that lead to α-helices. A simple kinetic model describes the rate of converting nonlocal HBs into α-helices. Torsional coordinate MD speeds folding by eliminating bond and angle degrees of freedom and reducing dynamical friction. Thus, the observed times of 80 to 500 ps are likely to be lower bounds on real rates. However, we believe the sequential steps observed here mirror those of real systems. When compensating for the effect of dynamic friction, the half live for α-helix formation of (Ala)_(20) is estimated to be 209 ps. Chapters 2 and 3 describe two trajectories of (Ala)_(20) folding into an α-helix. Different types of analyses are used to understand the process of formation and simplify the megabytes of information available in each trajectory. Chapter 2 illustrates a trajectory that forms an α-helix fast, whereas Chapter 3 describes a trajectory where helix formation was retarded by nonlocal HBs. These simulations attempt to elucidate the early events of protein folding. As elaborated in Chapter 1, the early events may be vital to controlling folding yield and the folding/aggregation partition.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Chemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Chan, Sunney I. (advisor)
  • Goddard, William A., III (co-advisor)
Thesis Committee:
  • Unknown, Unknown
Defense Date:5 August 1997
Funding AgencyGrant Number
Department of EnergyDE-FG36-93CH10581
National Science FoundationASC 92-17368 & CHE 95-12279
Record Number:CaltechTHESIS:10192009-084600422
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5306
Deposited By: Tony Diaz
Deposited On:04 Nov 2009 18:43
Last Modified:19 Apr 2021 22:39

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