7,528 research outputs found
Deriving amino acid contact potentials from their frequencies of occurence in proteins: a lattice model study
The possibility of deriving the contact potentials between amino acids from
their frequencies of occurence in proteins is discussed in evolutionary terms.
This approach allows the use of traditional thermodynamics to describe such
frequencies and, consequently, to develop a strategy to include in the
calculations correlations due to the spatial proximity of the amino acids and
to their overall tendency of being conserved in proteins. Making use of a
lattice model to describe protein chains and defining a "true" potential, we
test these strategies by selecting a database of folding model sequences,
deriving the contact potentials from such sequences and comparing them with the
"true" potential. Taking into account correlations allows for a markedly better
prediction of the interaction potentials
Protein-Mediated DNA Loops: Effects of Protein Bridge Size and Kinks
This paper focuses on the probability that a portion of DNA closes on itself
through thermal fluctuations. We investigate the dependence of this probability
upon the size r of a protein bridge and/or the presence of a kink at half DNA
length. The DNA is modeled by the Worm-Like Chain model, and the probability of
loop formation is calculated in two ways: exact numerical evaluation of the
constrained path integral and the extension of the Shimada and Yamakawa saddle
point approximation. For example, we find that the looping free energy of a 100
base pairs DNA decreases from 24 kT to 13 kT when the loop is closed by a
protein of r = 10 nm length. It further decreases to 5 kT when the loop has a
kink of 120 degrees at half-length.Comment: corrected typos and figures, references updated; 13 pages, 7 figures,
accepted for publication in Phys. Rev.
Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein
Computer simulation of the
conformations of short antigenic peptides (&lo
residues) either free or bound to their receptor,
the major histocompatibility complex (MHC)-
encoded glycoprotein H-2 Ld, was employed to
explain experimentally determined differences
in the antigenic activities within a set of related
peptides. Starting for each sequence from the
most probable conformations disclosed by a
pattern-recognition technique, several energyminimized
structures were subjected to molecular
dynamics simulations (MD) either in vacuo
or solvated by water molecules. Notably, antigenic
potencies were found to correlate to the
peptides propensity to form and maintain an
overall a-helical conformation through regular
i,i + 4 hydrogen bonds. Accordingly, less active
or inactive peptides showed a strong tendency
to form i,i+3 hydrogen bonds at their Nterminal
end. Experimental data documented
that the C-terminal residue is critical for interaction
of the peptide with H-2 Ld. This finding
could be satisfactorily explained by a 3-D
Q.S.A.R. analysis postulating interactions between
ligand and receptor by hydrophobic
forces. A 3-D model is proposed for the complex
between a high-affinity nonapeptide and the H-
2 Ld receptor. First, the H-2 Ld molecule was
built from X-ray coordinates of two homologous
proteins: HLA-A2 and HLA-Aw68, energyminimized
and studied by MD simulations. With
HLA-A2 as template, the only realistic simulation
was achieved for a solvated model with minor
deviations of the MD mean structure from
the X-ray conformation. Water simulation of the
H-2 Ld protein in complex with the antigenic
nonapeptide was then achieved with the template-
derived optimal parameters. The bound
peptide retains mainly its a-helical conformation
and binds to hydrophobic residues of H-2
Ld that correspond to highly polymorphic positions
of MHC proteins. The orientation of the
nonapeptide in the binding cleft is in accordance
with the experimentally determined distribution
of its MHC receptor-binding residues
(agretope residues). Thus, computer simulation was successfully employed to explain functional
data and predicts a-helical conformation
for the bound peptid
Cooperativity in two-state protein folding kinetics
We present a solvable model that predicts the folding kinetics of two-state
proteins from their native structures. The model is based on conditional chain
entropies. It assumes that folding processes are dominated by small-loop
closure events that can be inferred from native structures. For CI2, the src
SH3 domain, TNfn3, and protein L, the model reproduces two-state kinetics, and
it predicts well the average Phi-values for secondary structures. The barrier
to folding is the formation of predominantly local structures such as helices
and hairpins, which are needed to bring nonlocal pairs of amino acids into
contact.Comment: 9 pages, 6 figures, 1 tabl
Theory of Nucleosome Corkscrew Sliding in the Presence of Synthetic DNA Ligands
Histone octamers show a heat-induced mobility along DNA. Recent theoretical
studies have established two mechanisms that are qualitatively and
quantitatively compatible with in vitro experiments on nucleosome sliding:
Octamer repositiong through one-basepair twist defects and through ten-basepair
bulge defects. A recent experiment demonstrated that the repositioning is
strongly suppressed in the presence of minor-groove binding DNA ligands. In the
present study we give a quantitative theory for nucleosome repositioning in the
presence of such ligands. We show that the experimentally observed octamer
mobilities are consistent with the picture of bound ligands blocking the
passage of twist defects through the nucleosome. This strongly supports the
model of twist defects inducing a corkscrew motion of the nucleosome as the
underlying mechanism of nucleosome sliding. We provide a theoretical estimate
of the nucleosomal mobility without adjustable parameters, as a function of
ligand concentration, binding affinity, binding site orientiation, temperature
and DNA anisotropy. Having this mobility at hand we speculate about the
interaction between a nucleosome and a transcribing RNA polymerase and suggest
a novel mechanism that might account for polymerase induced nucleosome
repositioning.Comment: 23 pages, 4 figures, submitted to J. Mol. Bio
The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein
The folding pathway and rate coefficients of the folding of a knotted protein
are calculated for a potential energy function with minimal energetic
frustration. A kinetic transition network is constructed using the discrete
path sampling approach, and the resulting potential energy surface is
visualized by constructing disconnectivity graphs. Owing to topological
constraints, the low-lying portion of the landscape consists of three distinct
regions, corresponding to the native knotted state and to configurations where
either the N- or C-terminus is not yet folded into the knot. The fastest
folding pathways from denatured states exhibit early formation of the
N-terminus portion of the knot and a rate-determining step where the C-terminus
is incorporated. The low-lying minima with the N-terminus knotted and the
C-terminus free therefore constitute an off-pathway intermediate for this
model. The insertion of both the N- and C-termini into the knot occur late in
the folding process, creating large energy barriers that are the rate limiting
steps in the folding process. When compared to other protein folding proteins
of a similar length, this system folds over six orders of magnitude more
slowly.Comment: 19 page
Theoretical analysis of the role of chromatin interactions in long-range action of enhancers and insulators
Long-distance regulatory interactions between enhancers and their target
genes are commonplace in higher eukaryotes. Interposed boundaries or insulators
are able to block these long distance regulatory interactions. The mechanistic
basis for insulator activity and how it relates to enhancer
action-at-a-distance remains unclear. Here we explore the idea that topological
loops could simultaneously account for regulatory interactions of distal
enhancers and the insulating activity of boundary elements. We show that while
loop formation is not in itself sufficient to explain action at a distance,
incorporating transient non-specific and moderate attractive interactions
between the chromatin fibers strongly enhances long-distance regulatory
interactions and is sufficient to generate a euchromatin-like state. Under
these same conditions, the subdivision of the loop into two topologically
independent loops by insulators inhibits inter-domain interactions. The
underlying cause of this effect is a suppression of crossings in the contact
map at intermediate distances. Thus our model simultaneously accounts for
regulatory interactions at a distance and the insulator activity of boundary
elements. This unified model of the regulatory roles of chromatin loops makes
several testable predictions that could be confronted with \emph{in vitro}
experiments, as well as genomic chromatin conformation capture and fluorescent
microscopic approaches.Comment: 10 pages, originally submitted to an (undisclosed) journal in May
201
The intrinsic load-resisting capacity of kinesin
Conventional kinesin is a homodimeric motor protein that is capable of
walking unidirectionally along a cytoskeletal filament. While previous
experiments indicated unyielding unidirectionality against an opposing load up
to the so-called stall force, recent experiments also observed limited
processive backwalking under superstall loads. This theoretical study seeks to
elucidate the molecular mechanical basis for kinesin's steps over the full
range of external loads that can possibly be applied to the dimer. We found
that kinesin's load-resisting capacity is largely determined by a synergic
ratchet-and-pawl mechanism inherent in the dimer. Load susceptibility of this
inner molecular mechanical mechanism underlies kinesin's response to various
levels of external loads. Computational implementation of the mechanism enabled
us to rationalize major trends observed experimentally in kinesin's stalemate
and consecutive back steps. The study also predicts several distinct features
of kinesin's load-affected motility, which are seemingly counterintuitive but
readily verifiable by future experiment.Comment: 44 pages, 6 figure
- …