809 research outputs found
The architecture of the protein domain universe
Understanding the design of the universe of protein structures may provide
insights into protein evolution. We study the architecture of the protein
domain universe, which has been found to poses peculiar scale-free properties
(Dokholyan et al., Proc. Natl. Acad. Sci. USA 99: 14132-14136 (2002)). We
examine the origin of these scale-free properties of the graph of protein
domain structures (PDUG) and determine that that the PDUG is not modular, i.e.
it does not consist of modules with uniform properties. Instead, we find the
PDUG to be self-similar at all scales. We further characterize the PDUG
architecture by studying the properties of the hub nodes that are responsible
for the scale-free connectivity of the PDUG. We introduce a measure of the
betweenness centrality of protein domains in the PDUG and find a power-law
distribution of the betweenness centrality values. The scale-free distribution
of hubs in the protein universe suggests that a set of specific statistical
mechanics models, such as the self-organized criticality model, can potentially
identify the principal driving forces of molecular evolution. We also find a
gatekeeper protein domain, removal of which partitions the largest cluster into
two large sub-clusters. We suggest that the loss of such gatekeeper protein
domains in the course of evolution is responsible for the creation of new fold
families.Comment: 14 pages, 3 figure
Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis
Cu,Zn superoxide dismutase (SOD1) has been implicated in the familial form of
the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). It has been
suggested that mutant mediated SOD1 misfolding/aggregation is an integral part
of the pathology of ALS. We study the folding thermodynamics and kinetics of
SOD1 using a hybrid molecular dynamics approach. We reproduce the
experimentally observed SOD1 folding thermodynamics and find that the residues
which contribute the most to SOD1 thermal stability are also crucial for
apparent two-state folding kinetics. Surprisingly, we find that these residues
are located on the surface of the protein and not in the hydrophobic core.
Mutations in some of the identified residues are found in patients with the
disease. We argue that the identified residues may play an important role in
aggregation. To further characterize the folding of SOD1, we study the role of
cysteine residues in folding and find that non-native disulfide bond formation
may significantly alter SOD1 folding dynamics and aggregation propensity.Comment: 16 pages, 5 figure
Identifying the protein folding nucleus using molecular dynamics
Molecular dynamics simulations of folding in an off-lattice protein model reveal a nucleation scenario, in which a few well-defined contacts are formed with high probability in the transition state ensemble of conformations. Their appearance determines folding cooperativity and drives the model protein into its folded conformation. Amino acid residues participating in those contacts may serve as “accelerator pedals” used by molecular evolution to control protein folding rate.R01-52126 - PHS HHS; GM20251-01 - NIGMS NIH HHS; GM08291-09 - NIGMS NIH HHSAccepted manuscrip
Discrete molecular dynamics studies of the folding of a protein-like model
Background: Many attempts have been made to resolve in time the folding of
model proteins in computer simulations. Different computational approaches have
emerged. Some of these approaches suffer from the insensitivity to the
geometrical properties of the proteins (lattice models), while others are
computationally heavy (traditional MD).
Results: We use a recently-proposed approach of Zhou and Karplus to study the
folding of the protein model based on the discrete time molecular dynamics
algorithm. We show that this algorithm resolves with respect to time the
folding --- unfolding transition. In addition, we demonstrate the ability to
study the coreof the model protein.
Conclusion: The algorithm along with the model of inter-residue interactions
can serve as a tool to study the thermodynamics and kinetics of protein models.Comment: 15 pages including 20 figures (Folding & Design in press
Protein Evolution within a Structural Space
Understanding of the evolutionary origins of protein structures represents a
key component of the understanding of molecular evolution as a whole. Here we
seek to elucidate how the features of an underlying protein structural "space"
might impact protein structural evolution. We approach this question using
lattice polymers as a completely characterized model of this space. We develop
a measure of structural comparison of lattice structures that is analgous to
the one used to understand structural similarities between real proteins. We
use this measure of structural relatedness to create a graph of lattice
structures and compare this graph (in which nodes are lattice structures and
edges are defined using structural similarity) to the graph obtained for real
protein structures. We find that the graph obtained from all compact lattice
structures exhibits a distribution of structural neighbors per node consistent
with a random graph. We also find that subgraphs of 3500 nodes chosen either at
random or according to physical constraints also represent random graphs. We
develop a divergent evolution model based on the lattice space which produces
graphs that, within certain parameter regimes, recapitulate the scale-free
behavior observed in similar graphs of real protein structures.Comment: 27 pages, 7 figure
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