Peptide folding and local unfolding of SOD1 in the presence of interacting macromolecular crowders - a Monte Carlo approach
Author
Summary, in English
A protein chain often folds into a functional, specific three dimensional structure. Failure
in this process can in some cases lead to disease, e.g. the misfolding disease ALS. The
mechanisms behind the folding has mostly been studied under dilute conditions. However,
in the natural cellular environment of proteins, the concentration of macromolecules is high
and it is believed that this affects various processes in the cells, such as the folding, but the
underlying mechanism is largely unknown.
In this thesis we present a Monte Carlo based simulation approach to study the effects of
crowding. We investigate the equilibrium properties of two small peptides in the presence
of different types of crowders, both interacting protein crowders and non-interacting hard-
spheres. In our simulations with protein crowders, we find that purely steric effects can not
alone explain the observed behaviour. The peptides can be either stabilized or destabilized,
depending on their specific interaction with the crowders.
We also apply the same simulation scheme to study local unfolding of the ALS-linked protein
superoxide dismutase 1, SOD1, in the presence of crowders. We compare this with results
obtained without crowders. The crowders are found to have little effect on the barrel stability,
partly due to interaction with the functional loop regions of SOD1. In both the crowder and
crowder-free simulations, the instability of the second
-sheet of the SOD1 molecule is more
pronounced than that of the first sheet.
Detailed knowledge of how the SOD1 molecule specifically responds to its environment opens
up for the possibility to understand the mechanisms behind its misfolding, believed to be
important in the initial events of certain forms of ALS
in this process can in some cases lead to disease, e.g. the misfolding disease ALS. The
mechanisms behind the folding has mostly been studied under dilute conditions. However,
in the natural cellular environment of proteins, the concentration of macromolecules is high
and it is believed that this affects various processes in the cells, such as the folding, but the
underlying mechanism is largely unknown.
In this thesis we present a Monte Carlo based simulation approach to study the effects of
crowding. We investigate the equilibrium properties of two small peptides in the presence
of different types of crowders, both interacting protein crowders and non-interacting hard-
spheres. In our simulations with protein crowders, we find that purely steric effects can not
alone explain the observed behaviour. The peptides can be either stabilized or destabilized,
depending on their specific interaction with the crowders.
We also apply the same simulation scheme to study local unfolding of the ALS-linked protein
superoxide dismutase 1, SOD1, in the presence of crowders. We compare this with results
obtained without crowders. The crowders are found to have little effect on the barrel stability,
partly due to interaction with the functional loop regions of SOD1. In both the crowder and
crowder-free simulations, the instability of the second
-sheet of the SOD1 molecule is more
pronounced than that of the first sheet.
Detailed knowledge of how the SOD1 molecule specifically responds to its environment opens
up for the possibility to understand the mechanisms behind its misfolding, believed to be
important in the initial events of certain forms of ALS
Publishing year
2016
Language
English
Document type
Dissertation
Publisher
Lund University, Faculty of Science, Department of Astronomy and Theoretical Physics
Topic
- Other Physics Topics
Keywords
- Monte Carlo simulations
- protein folding
- SOD1
- crowding
- Fysicumarkivet A:2016:Bille
Status
Published
Supervisor
ISBN/ISSN/Other
- ISBN: 978-91-7623-849-3
- ISBN: 978-91-7623-848-6
Defence date
17 June 2016
Defence time
13:15
Defence place
Lund Observatory, Lundmark Lecture hall, Sölvegatan 27, Lund
Opponent
- Alexander Schug (Dr.)