211 research outputs found
Optimization and evaluation of a coarse-grained model of protein motion using X-ray crystal data
Simple coarse-grained models, such as the Gaussian Network Model, have been
shown to capture some of the features of equilibrium protein dynamics. We
extend this model by using atomic contacts to define residue interactions and
introducing more than one interaction parameter between residues. We use
B-factors from 98 ultra-high resolution X-ray crystal structures to optimize
the interaction parameters. The average correlation between GNM fluctuation
predictions and the B-factors is 0.64 for the data set, consistent with a
previous large-scale study. By separating residue interactions into covalent
and noncovalent, we achieve an average correlation of 0.74, and addition of
ligands and cofactors further improves the correlation to 0.75. However,
further separating the noncovalent interactions into nonpolar, polar, and mixed
yields no significant improvement. The addition of simple chemical information
results in better prediction quality without increasing the size of the
coarse-grained model.Comment: 18 pages, 4 figures, 1 supplemental file (cnm_si.tex
Thermodynamically Important Contacts in Folding of Model Proteins
We introduce a quantity, the entropic susceptibility, that measures the
thermodynamic importance-for the folding transition-of the contacts between
amino acids in model proteins. Using this quantity, we find that only one
equilibrium run of a computer simulation of a model protein is sufficient to
select a subset of contacts that give rise to the peak in the specific heat
observed at the folding transition. To illustrate the method, we identify
thermodynamically important contacts in a model 46-mer. We show that only about
50% of all contacts present in the protein native state are responsible for the
sharp peak in the specific heat at the folding transition temperature, while
the remaining 50% of contacts do not affect the specific heat.Comment: 5 pages, 5 figures; to be published in PR
Native geometry and the dynamics of protein folding
In this paper we investigate the role of native geometry on the kinetics of
protein folding based on simple lattice models and Monte Carlo simulations.
Results obtained within the scope of the Miyazawa-Jernigan indicate the
existence of two dynamical folding regimes depending on the protein chain
length. For chains larger than 80 amino acids the folding performance is
sensitive to the native state's conformation. Smaller chains, with less than 80
amino acids, fold via two-state kinetics and exhibit a significant correlation
between the contact order parameter and the logarithmic folding times. In
particular, chains with N=48 amino acids were found to belong to two broad
classes of folding, characterized by different cooperativity, depending on the
contact order parameter. Preliminary results based on the G\={o} model show
that the effect of long range contact interaction strength in the folding
kinetics is largely dependent on the native state's geometry.Comment: Proceedings of the BIFI 2004 - I International Conference, Zaragoza
(Spain) Biology after the genome: a physical view. To appear in Biophysical
Chemistr
On the optimal contact potential of proteins
We analytically derive the lower bound of the total conformational energy of
a protein structure by assuming that the total conformational energy is well
approximated by the sum of sequence-dependent pairwise contact energies. The
condition for the native structure achieving the lower bound leads to the
contact energy matrix that is a scalar multiple of the native contact matrix,
i.e., the so-called Go potential. We also derive spectral relations between
contact matrix and energy matrix, and approximations related to one-dimensional
protein structures. Implications for protein structure prediction are
discussed.Comment: 5 pages, text onl
Molecular dynamics of C-peptide of ribonuclease A studied by replica-exchange Monte Carlo method and diffusion theory
Generalized-ensemble algorithm and diffusion theory have been combined in
order to compute the dynamical properties monitored by nuclear magnetic
resonance experiments from efficient and reliable evaluation of statistical
averages. Replica-exchange Monte Carlo simulations have been performed with a
C-peptide analogue of ribonuclease A, and Smoluchowski diffusion equations have
been applied. A fairly good agreement between the calculated and measured
H-NOESY NMR cross peaks has been obtained. The combination of these
advanced and continuously improving statistical tools allows the calculation of
a wide variety of dynamical properties routinely obtained by experiments.Comment: 17 pages, 5 figures, (LaTeX); Chemical Physics Letters, in pres
Thermodynamics of alpha- and beta-structure formation in proteins
An atomic protein model with a minimalistic potential is developed and then
tested on an alpha-helix and a beta-hairpin, using exactly the same parameters
for both peptides. We find that melting curves for these sequences to a good
approximation can be described by a simple two-state model, with parameters
that are in reasonable quantitative agreement with experimental data. Despite
the apparent two-state character of the melting curves, the energy
distributions are found to lack a clear bimodal shape, which is discussed in
some detail. We also perform a Monte Carlo-based kinetic study and find, in
accord with experimental data, that the alpha-helix forms faster than the
beta-hairpin.Comment: 18 pages, 4 figure
Two-state folding over a weak free-energy barrier
We present a Monte Carlo study of a model protein with 54 amino acids that
folds directly to its native three-helix-bundle state without forming any
well-defined intermediate state. The free-energy barrier separating the native
and unfolded states of this protein is found to be weak, even at the folding
temperature. Nevertheless, we find that melting curves to a good approximation
can be described in terms of a simple two-state system, and that the relaxation
behavior is close to single exponential. The motion along individual reaction
coordinates is roughly diffusive on timescales beyond the reconfiguration time
for an individual helix. A simple estimate based on diffusion in a square-well
potential predicts the relaxation time within a factor of two.Comment: 22 pages, 5 figure
Quantum mechanical calculation of the effects of stiff and rigid constraints in the conformational equilibrium of the Alanine dipeptide
If constraints are imposed on a macromolecule, two inequivalent classical
models may be used: the stiff and the rigid one. This work studies the effects
of such constraints on the Conformational Equilibrium Distribution (CED) of the
model dipeptide HCO-L-Ala-NH2 without any simplifying assumption. We use ab
initio Quantum Mechanics calculations including electron correlation at the MP2
level to describe the system, and we measure the conformational dependence of
all the correcting terms to the naive CED based in the Potential Energy Surface
(PES) that appear when the constraints are considered. These terms are related
to mass-metric tensors determinants and also occur in the Fixman's compensating
potential. We show that some of the corrections are non-negligible if one is
interested in the whole Ramachandran space. On the other hand, if only the
energetically lower region, containing the principal secondary structure
elements, is assumed to be relevant, then, all correcting terms may be
neglected up to peptides of considerable length. This is the first time, as far
as we know, that the analysis of the conformational dependence of these
correcting terms is performed in a relevant biomolecule with a realistic
potential energy function.Comment: 37 pages, 4 figures, LaTeX, BibTeX, AMSTe
Testing simplified protein models of the hPin1 WW domain
The WW domain of the human Pin1 protein for its simple topology and the large
amount of experimental data is an ideal candidate to assess theoretical
approaches to protein folding. The purpose of the present work is to compare
the reliability of the chemically-based Sorenson/Head-Gordon (SHG) model and a
standard native centric model in reproducing through molecular dynamics
simulations some of the well known features of the folding transition of this
small domain. Our results show that the G\={o} model correctly reproduces the
cooperative, two-state, folding mechanism of the WW-domain, while the SHG model
predicts a transition occurring in two stages: a collapse followed by a
structural rearrangement. The lack of a cooperative folding in the SHG
simulations appears to be related to the non-funnel shape of the energy
landscape featuring a partitioning of the native valley in sub-basins
corresponding to different chain chiralities. However the SHG approach remains
more reliable in estimating the -values with respect to G\={o}-like
description. This may suggest that the WW-domain folding process is stirred by
energetic and topological factors as well, and it highlights the better
suitability of chemically-based models in simulating mutations.Comment: RevTex4: 12 pages and 13 eps-figure file
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