32 research outputs found
Thermodynamic stability of folded proteins against mutations
By balancing the average energy gap with its typical change due to mutations
for protein-like heteropolymers with M residues, we show that native states are
unstable to mutations on a scale M* ~ (lambda/sigma_mu)^(1/zeta_s), where
lambda is the dispersion in the interaction free energies and sigma_mu their
typical change. Theoretical bounds and numerical estimates (based on complete
enumeration on four lattices) of the instability exponent zeta_s are given. Our
analysis suggests that a limiting size of single-domain proteins should exist,
and leads to the prediction that small proteins are insensitive to random
mutations.Comment: 5 pages, 3 figures, to be published in Physical Review Letter
Influence of Hydrodynamic Interactions on Mechanical Unfolding of Proteins
We incorporate hydrodynamic interactions in a structure-based model of
ubiquitin and demonstrate that the hydrodynamic coupling may reduce the peak
force when stretching the protein at constant speed, especially at larger
speeds. Hydrodynamic interactions are also shown to facilitate unfolding at
constant force and inhibit stretching by fluid flows.Comment: to be published in Journal of Physics: Condensed Matte
Folding, Design and Determination of Interaction Potentials Using Off-Lattice Dynamics of Model Heteropolymers
We present the results of a self-consistent, unified molecular dynamics study
of simple model heteropolymers in the continuum with emphasis on folding,
sequence design and the determination of the interaction parameters of the
effective potential between the amino acids from the knowledge of the native
states of the designed sequences.Comment: 8 pages, 3 Postscript figures, uses RevTeX. Submitted to Physical
Review Letter
Modeling study on the validity of a possibly simplified representation of proteins
The folding characteristics of sequences reduced with a possibly simplified
representation of five types of residues are shown to be similar to their
original ones with the natural set of residues (20 types or 20 letters). The
reduced sequences have a good foldability and fold to the same native structure
of their optimized original ones. A large ground state gap for the native
structure shows the thermodynamic stability of the reduced sequences. The
general validity of such a five-letter reduction is further studied via the
correlation between the reduced sequences and the original ones. As a
comparison, a reduction with two letters is found not to reproduce the native
structure of the original sequences due to its homopolymeric features.Comment: 6 pages with 4 figure
Mechanical Strength of 17 134 Model Proteins and Cysteine Slipknots
A new theoretical survey of proteins' resistance to constant speed stretching
is performed for a set of 17 134 proteins as described by a structure-based
model. The proteins selected have no gaps in their structure determination and
consist of no more than 250 amino acids. Our previous studies have dealt with
7510 proteins of no more than 150 amino acids. The proteins are ranked
according to the strength of the resistance. Most of the predicted top-strength
proteins have not yet been studied experimentally. Architectures and folds
which are likely to yield large forces are identified. New types of potent
force clamps are discovered. They involve disulphide bridges and, in
particular, cysteine slipknots. An effective energy parameter of the model is
estimated by comparing the theoretical data on characteristic forces to the
corresponding experimental values combined with an extrapolation of the
theoretical data to the experimental pulling speeds. These studies provide
guidance for future experiments on single molecule manipulation and should lead
to selection of proteins for applications. A new class of proteins, involving
cystein slipknots, is identified as one that is expected to lead to the
strongest force clamps known. This class is characterized through molecular
dynamics simulations.Comment: 40 pages, 13 PostScript figure
Capturing the essence of folding and functions of biomolecules using Coarse-Grained Models
The distances over which biological molecules and their complexes can
function range from a few nanometres, in the case of folded structures, to
millimetres, for example during chromosome organization. Describing phenomena
that cover such diverse length, and also time scales, requires models that
capture the underlying physics for the particular length scale of interest.
Theoretical ideas, in particular, concepts from polymer physics, have guided
the development of coarse-grained models to study folding of DNA, RNA, and
proteins. More recently, such models and their variants have been applied to
the functions of biological nanomachines. Simulations using coarse-grained
models are now poised to address a wide range of problems in biology.Comment: 37 pages, 8 figure
The Effect of Macromolecular Crowding, Ionic Strength and Calcium Binding on Calmodulin Dynamics
The flexibility in the structure of calmodulin (CaM) allows its binding to
over 300 target proteins in the cell. To investigate the structure-function
relationship of CaM, we combined methods of computer simulation and experiments
based on circular dichroism (CD) to investigate the structural characteristics
of CaM that influence its target recognition in crowded cell-like conditions.
We developed a unique multiscale solution of charges computed from quantum
chemistry, together with protein reconstruction, coarse-grained molecular
simulations, and statistical physics, to represent the charge distribution in
the transition from apoCaM to holoCaM upon calcium binding. Computationally, we
found that increased levels of macromolecular crowding, in addition to calcium
binding and ionic strength typical of that found inside cells, can impact the
conformation, helicity and the EF hand orientation of CaM. Because EF hand
orientation impacts the affinity of calcium binding and the specificity of
CaM's target selection, our results may provide unique insight into
understanding the promiscuous behavior of calmodulin in target selection inside
cells.Comment: Accepted to PLoS Comp Biol, 201