11,687 research outputs found
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
Kinetics of the Wako-Saito-Munoz-Eaton Model of Protein Folding
We consider a simplified model of protein folding, with binary degrees of
freedom, whose equilibrium thermodynamics is exactly solvable. Based on this
exact solution, the kinetics is studied in the framework of a local equilibrium
approach, for which we prove that (i) the free energy decreases with time, (ii)
the exact equilibrium is recovered in the infinite time limit, and (iii) the
folding rate is an upper bound of the exact one. The kinetics is compared to
the exact one for a small peptide and to Monte Carlo simulations for a longer
protein, then rates are studied for a real protein and a model structure.Comment: 4 pages, 4 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
Kinetics and Thermodynamics of Membrane Protein Folding
Understanding protein folding has been one of the great challenges in
biochemistry and molecular biophysics. Over the past 50 years, many
thermodynamic and kinetic studies have been performed addressing the stability
of globular proteins. In comparison, advances in the membrane protein folding
field lag far behind. Although membrane proteins constitute about a third of
the proteins encoded in known genomes, stability studies on membrane proteins
have been impaired due to experimental limitations. Furthermore, no systematic
experimental strategies are available for folding these biomolecules in vitro.
Common denaturing agents such as chaotropes usually do not work on helical
membrane proteins, and ionic detergents have been successful denaturants only
in few cases. Refolding a membrane protein seems to be a craftsman work, which
is relatively straightforward for transmembrane {\beta}-barrel proteins but
challenging for {\alpha}-helical membrane proteins. Additional complexities
emerge in multidomain membrane proteins, data interpretation being one of the
most critical. In this review, we will describe some recent efforts in
understanding the folding mechanism of membrane proteins that have been
reversibly refolded allowing both thermodynamic and kinetic analysis. This
information will be discussed in the context of current paradigms in the
protein folding field
Cooperativity and Stability in a Langevin Model of Protein Folding
We present two simplified models of protein dynamics based on Langevin's
equation of motion in a viscous medium. We explore the effect of the potential
energy function's symmetry on the kinetics and thermodynamics of simulated
folding. We find that an isotropic potential energy function produces, at best,
a modest degree of cooperativity. In contrast, a suitable anisotropic potential
energy function delivers strong cooperativity.Comment: 45 pages, 16 figures, 2 tables. LaTeX. Submitted to the Journal of
Chemical Physic
Exact Solution of the Munoz-Eaton Model for Protein Folding
A transfer-matrix formalism is introduced to evaluate exactly the partition
function of the Munoz-Eaton model, relating the folding kinetics of proteins of
known structure to their thermodynamics and topology. This technique can be
used for a generic protein, for any choice of the energy and entropy
parameters, and in principle allows the model to be used as a first tool to
characterize the dynamics of a protein of known native state and equilibrium
population. Applications to a -hairpin and to protein CI-2, with
comparisons to previous results, are also shown.Comment: 4 pages, 5 figures, RevTeX 4. To be published in Phys. Rev. Let
- …