345 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
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
Emergence of Protein Fold Families through Rational Design
Diverse proteins with similar structures are grouped into families of homologs and analogs, if their sequence similarity is higher or lower, respectively, than 20%–30%. It was suggested that protein homologs and analogs originate from a common ancestor and diverge in their distinct evolutionary time scales, emerging as a consequence of the physical properties of the protein sequence space. Although a number of studies have determined key signatures of protein family organization, the sequence-structure factors that differentiate the two evolution-related protein families remain unknown. Here, we stipulate that subtle structural changes, which appear due to accumulating mutations in the homologous families, lead to distinct packing of the protein core and, thus, novel compositions of core residues. The latter process leads to the formation of distinct families of homologs. We propose that such differentiation results in the formation of analogous families. To test our postulate, we developed a molecular modeling and design toolkit, Medusa, to computationally design protein sequences that correspond to the same fold family. We find that analogous proteins emerge when a backbone structure deviates only 1–2 Å root-mean-square deviation from the original structure. For close homologs, core residues are highly conserved. However, when the overall sequence similarity drops to ~25%–30%, the composition of core residues starts to diverge, thereby forming novel families of protein homologs. This direct observation of the formation of protein homologs within a specific fold family supports our hypothesis. The conservation of amino acids in designed sequences recapitulates that of the naturally occurring sequences, thereby validating our computational design methodology
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