MINISTRY OF EDUCATION VIETNAM ACADEMY
AND TRAINING OF SCIENCE AND TECHNOLOGY
GRADUATE UNIVERSITY SCIENCE AND TECHNOLOGY
———————
NGUYEN BA HUNG
THE ROLE OF HYDROPHOBIC AND POLAR SEQUENCE
ON FOLDING MECHANISMS OF PROTEINS AND
AGGREGATION OF PEPTIDES
Major: Theoretical and computational physics
Code: 9 44 01 03
SUMMARY OF PHYSICS DOCTORAL THESIS
HANOI −2018
INTRODUCTION
The problem of protein folding has always been of prime concern in molecular
biology. Under normal physiological conditions, most proteins acquire well defined
compact three dimensional shapes, known as the native conformations, at which
they are biologically active. When proteins are unfolding or misfolding, they
not only lose their inherent biological activity but they can also aggregate into
insoluble fibrils structures called amyloids which are known to be involved in
many degenerative diseases like Alzheimer’s disease, Parkinson’s disease, type
2 diabetes, cerebral palsy, mad cow disease etc. Thus, determining the folded
structure and clarifying the mechanism of folding of the protein plays an important
role in our understanding of the living organism as well as the human health.
Protein aggregation and amyloid formation have also been studied extensively
in recent years. Studies have led to the hypothesis that amyloid is the general
state of all proteins and is the fundamental state of the system when proteins
can form intermolecular interactions. Thus, the tendency for aggregation and for-
mation amyloid persists for all proteins and is a trend towards competition with
protein folding. However, experiments have also shown that possibility of aggre-
gation and aggregation rates depend on solvent conditions and on the amino acid
sequence of proteins. Some studies have shown that small amino acid sequences
in the protein chain may have a significant effect on the aggregation ability. As
a result, knowledge about the link between amino acid sequence and possibility
of aggregation is essential for understanding amyloid-related diseases as well as
finding a way to treat them.
Although all-atom simulations are now widely used molecular biology, the
application of these methods in the study of protein folding problem is not feasible
due to the limits of computer speed. A suitable approach to the protein folding
problem is to use simple theoretical models. There are quite a number of models
with different ideas and levels of simplicity, but most notably the Go model and
the HP network model and tube model.
Considerations of tubular polymer suggest that tubular symmetry is a fun-
damental feature of protein molecules which forms the secondary structures of
proteins (αand β). Base on this idea, the tube model for the protein was de-
veloped by Hoang and Maritan’s team and proposed in 2004. The results of the
tube model suggest that this is a simple model and can describes well many of the
basic features of protein. The tube model is also the only current model that can
simultaneously be used for the study of both folding and aggregation processes.
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In this thesis, we use a tube model to study the role of hydrophobic and
polar sequence on folding mechanism of proteins and aggregation of peptides.
Spatial fill of the tubular polymer and hydrogen bonds in the model play the
role of background interactions and are independent of the amino acid sequence.
The amino acid sequence we consider in the simplified model consists of two
types of amino acids, hydrophobic (H) and polar (P). To study the effect of HP
sequence on the folding process, we will compare the folding properties of the
tube model using the hydrophobic interaction (HP tube model) with tube model
using the pairing interaction which is similar to the Go model (Go tube model).
This comparison helps to clarify the role of non-native interactions in non-native
interactions. To study the role of the HP sequence on aggregation of protein, we
will compare the possibility of aggregation of peptide sequences with different HP
sequences including the consideration of the shape of the aggregation structures
and the properties of aggregation transition phase. In addition, in the study of
protein aggregation, we propose an improved model for hydrophobic interaction
in the tube model by taking into account the orientation of the side chains of
hydrophobic amino acids. Our research shows that this improved model allows
for obtaining highly ordered, long-chain aggregation structures like amyloid fibrils.
1. The objectives of the thesis:
The aim of the studies is to gain fundamental understanding of the role of
hydrophobic and polar sequence on folding mechanism of proteins and aggre-
gation of peptides
2. The main contents of the thesis:
The general understanding of protein and protein folding, protein aggregation
is introduced in chapters 1, 2 of this thesis. Chapter 3 presents the methods
used to simulate and analyze the data. The obtained results of role of HP
sequence for protein folding are presented in chapter 4. The results of role of
HP sequence for protein aggregation are presented in chapter 5.
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Chapter 1
Protein folding
1.1 Structural properties of proteins
Proteins are macromolecules that are synthesized in the cell and responsible
for the most basic and important aspects of life. Proteins are polymers (polypep-
tides) formed from sequences of 20 diffirent types of amino acids, the monomers
of the polymer. The amino acids in the protein differ only in their side chains
and are linked together through peptide bonds that form a linear sequence in a
particular order.
Under normal physiological conditions, most proteins acquire well defined
compact three dimensional shapes, knows as the native conformations, at which
they are biologically active.
The amino acid sequence in the protein determines the structure and function
of the protein. Proteins has four types of structure.
Primary structure: It is just the chemical sequence of amino acids along the
backbone of the protein. These amino acid in chain linked together by peptide
bonds.
Secondary structure is the spatial arrangement of amino acids. There are two
such types of structures: the α-helices and the β-sheets. This kind of structure
which maximize the number of hydrogen bonds (H-bonds) between the CO and
the NH groups of the backbone.
Tertiary structure: A compact packing of the secondary structures comprises
tertiary structures. Usually, theses are the full three dimensional structures of
proteins. Tertiary structures of large proteins are usually composed of several
domains.
Quaternary structure: Some proteins are composed of more than one polypep-
tide chain. The polypeptide chains may have identical or different amino acid
sequences depending on the protein. Each peptide is called a subunit and has its
own tertiary structure. The spatial arrangement of these subunits in the protein
is called quaternary structure
There are a number of semi-empirical interactions that are introduced by
chemists and physicists to describe interactions in proteins: disulfide bridges,
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Coulomb interactions, Hydrogen bonds, Van der Waals interactions, Hydrophobic
interactions.
1.2 Protein folding phenomenon
Once translated by a ribosome, each polypeptide folds into its characteristic
three-dimensional structure from a random coil. Since the fold is maintained by a
network of interactions between amino acids in the polypeptide, the native state
of the protein chain is determined by the amino acid sequence (hypothesis of
thermodynamics).
1.3 Paradox of Levinthal
Levinthal paradox which addresses the question: how can proteins possibly
find their native state if the number of possible conformations of a polypeptide
chain is astronomically large?
1.4 Folding funnel
Based on theoretical and empirical research findings, Onuchic and his col-
leagues have come up with the idea of the folding funnel as depicted in Figure
1.1. The folding process of the protein in the funnel is the simultaneous reduc-
tion of both energy and entropy. As the protein begins to fold, the free energy
decreases and the number of configurations decreases (characterized by reduced
well width).
N
folding
entropy
g
energy
Figure 1.1: The diagram sketches of funnel describes the protein folding energy lanscape
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