Jiménez Roldán, J. E. (José Emilio) (2012) Rigidity analysis of protein structures and rapid simulations of protein motion. PhD thesis, University of Warwick.

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Abstract

It is a common goal in biophysics to understand protein structural properties
and their relationship to protein function. I investigated protein structural
properties using three coarse graining methods: a rigidity analysis method First, a
geometric simulation method Froda and normal mode analysis as implemented in
Elnemo to identify the protein directions of motion. Furthermore, I also compared
the results between the coarse graining methods with the results from molecular
dynamics and from experiments that I carried out. The results from the rigidity
analysis across a set of protein families presented in chapter 3 highlighted two different
patterns of protein rigidity loss, i.e. "sudden" and "gradual". It was found
that theses characteristic patterns were in line with the rigidity distribution of glassy
networks. The simulations of protein motion by merging flexibility, rigidity and normal
mode analyses presented in chapter 4 were able to identify large conformational
changes of proteins using minimal computational resources. I investigated the use
of RMSD as a measure to characterise protein motion and showed that, despite it
is a good measure to identify structural differences when comparing the same protein,
the use of extensive RMSD better captures the extend of motion of a protein
structure. The in-depth investigation of yeast PDI mobility presented in chapter
5 confirmed former experimental results that predicted a large conformational
change for this enzyme. Furthermore, the results predicted: a characteristic rigidity
distribution for yeast PDI, a minimum and a maximum active site distance and a
relationship between the energy cutoff, i.e. the number of hydrogen bonds part of the
network of bonds, and protein mobility. The results obtained were tested against
molecular dynamics simulations in chapter 6. The MD simulation also showed a
large conformational change for yeast PDI but with a slightly different minimum
and maximum inter-cysteine distance. Furthermore, MD was able to reveal new
data, i.e. the most likely inter-cysteine distance. In order to test the accuracy of the
coarse graining and MD simulations I carried out cross-linking experiments to test
the minimum inter-cysteine distance predictions. The results presented in chapter
7 show that human PDI minimum distance is below 12Å whereas the yeast PDI
minimum distance must be above 12Å as no cross-linking structures where found
with the available (12Å long) cross-linkers.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QH Natural history > QH301 Biology
Library of Congress Subject Headings (LCSH):	Proteins -- Structure, Proteins -- Computer simulation
Official Date:	July 2012
Dates:	Date Event July 2012 Submitted
Institution:	University of Warwick
Theses Department:	Department of Physics ; School of Life Sciences
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Roemer, Rudolf A. ; Freedman, R. B.
Extent:	xiv, 1, 118 leaves : ill., charts
Language:	eng

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