PROTEIN FOLD SWITCHING IN COARSE-GRAINED MODELS
Author
Summary, in English
Proteins carry out the instructions encoded in genes and are crucial for many important tasks
in the living organism. Often the specific three dimensional structure, or fold, of a protein
enables it to carry out a given task. It is an open question whether protein folds have arisen
independently or whether mutations to existing protein sequences have caused switches to
new folds.
In the main part of this thesis, consisting of papers I-III, we have investigated protein fold
switching in response to point mutations using computer simuations of coarse-grained mod-
els. The basic idea behind coarse-grained models is that by simplifying the description of
proteins, the structure of a large number of model sequences can be determined with reduced
computational effort. In paper I we exhaustively enumerate protein sequence-structure space
in a simple hydrophobic/polar lattice model, exceeding previous enumerations. This enables
us in particular to analyze mutational pathways and their stability. In paper II we investigate
how protein function changes along a mutational pathway with a sharp switch in fold, using
the continuous Cβ model. We find that the switch in fold and preferred binding partner do
not coincide and that the change in function is more gradual than the switch in fold. In paper
III we hypothesize that fold switches between similar protein folds involve bistable sequences,
while fold switches between dissimilar folds occur within a single mutation. In particular, we
show that while the fold switches are driven by changes in energy, configurational entropy
can play a significant role in determining when a switch occurs. In paper IV, we analyze
the hybrid Monte Carlo method for biomolecular simulations, which is based on numerical
integration of Newton’s equations of motion. We optimize this method for three systems and
find that a nonuniform integration step can reduce the integration error.
in the living organism. Often the specific three dimensional structure, or fold, of a protein
enables it to carry out a given task. It is an open question whether protein folds have arisen
independently or whether mutations to existing protein sequences have caused switches to
new folds.
In the main part of this thesis, consisting of papers I-III, we have investigated protein fold
switching in response to point mutations using computer simuations of coarse-grained mod-
els. The basic idea behind coarse-grained models is that by simplifying the description of
proteins, the structure of a large number of model sequences can be determined with reduced
computational effort. In paper I we exhaustively enumerate protein sequence-structure space
in a simple hydrophobic/polar lattice model, exceeding previous enumerations. This enables
us in particular to analyze mutational pathways and their stability. In paper II we investigate
how protein function changes along a mutational pathway with a sharp switch in fold, using
the continuous Cβ model. We find that the switch in fold and preferred binding partner do
not coincide and that the change in function is more gradual than the switch in fold. In paper
III we hypothesize that fold switches between similar protein folds involve bistable sequences,
while fold switches between dissimilar folds occur within a single mutation. In particular, we
show that while the fold switches are driven by changes in energy, configurational entropy
can play a significant role in determining when a switch occurs. In paper IV, we analyze
the hybrid Monte Carlo method for biomolecular simulations, which is based on numerical
integration of Newton’s equations of motion. We optimize this method for three systems and
find that a nonuniform integration step can reduce the integration error.
Publishing year
2014
Language
English
Document type
Dissertation
Publisher
Department of Astronomy and Theoretical Physics, Lund University
Topic
- Biophysics
Keywords
- Fysicumarkivet A:2014:Holzgräfe
- coarse-grained model
- protein folding
- evolution
- fold switching
Status
Published
Supervisor
- Stefan Wallin
ISBN/ISSN/Other
- ISBN: 978-91-7623-074-9
Defence date
26 September 2014
Defence time
10:15
Defence place
Lundmarksalen, Astronomihuset
Opponent
- Patrícia Faísca