34,222 research outputs found
Protein structural variation in computational models and crystallographic data
Normal mode analysis offers an efficient way of modeling the conformational
flexibility of protein structures. Simple models defined by contact topology,
known as elastic network models, have been used to model a variety of systems,
but the validation is typically limited to individual modes for a single
protein. We use anisotropic displacement parameters from crystallography to
test the quality of prediction of both the magnitude and directionality of
conformational variance. Normal modes from four simple elastic network model
potentials and from the CHARMM forcefield are calculated for a data set of 83
diverse, ultrahigh resolution crystal structures. While all five potentials
provide good predictions of the magnitude of flexibility, the methods that
consider all atoms have a clear edge at prediction of directionality, and the
CHARMM potential produces the best agreement. The low-frequency modes from
different potentials are similar, but those computed from the CHARMM potential
show the greatest difference from the elastic network models. This was
illustrated by computing the dynamic correlation matrices from different
potentials for a PDZ domain structure. Comparison of normal mode results with
anisotropic temperature factors opens the possibility of using ultrahigh
resolution crystallographic data as a quantitative measure of molecular
flexibility. The comprehensive evaluation demonstrates the costs and benefits
of using normal mode potentials of varying complexity. Comparison of the
dynamic correlation matrices suggests that a combination of topological and
chemical potentials may help identify residues in which chemical forces make
large contributions to intramolecular coupling.Comment: 17 pages, 4 figure
Mapping energy transport networks in proteins
The response of proteins to chemical reactions or impulsive excitation that
occurs within the molecule has fascinated chemists for decades. In recent years
ultrafast X-ray studies have provided ever more detailed information about the
evolution of protein structural change following ligand photolysis, and
time-resolved IR and Raman techniques, e.g., have provided detailed pictures of
the nature and rate of energy transport in peptides and proteins, including
recent advances in identifying transport through individual amino acids of
several heme proteins. Computational tools to locate energy transport pathways
in proteins have also been advancing. Energy transport pathways in proteins
have since some time been identified by molecular dynamics (MD) simulations,
and more recent efforts have focused on the development of coarse graining
approaches, some of which have exploited analogies to thermal transport in
other molecular materials. With the identification of pathways in proteins and
protein complexes, network analysis has been applied to locate residues that
control protein dynamics and possibly allostery, where chemical reactions at
one binding site mediate reactions at distance sites of the protein. In this
chapter we review approaches for locating computationally energy transport
networks in proteins. We present background into energy and thermal transport
in condensed phase and macromolecules that underlies the approaches we discuss
before turning to a description of the approaches themselves. We also
illustrate the application of the computational methods for locating energy
transport networks and simulating energy dynamics in proteins with several
examples
High-resolution NMR studies of structure and dynamics of human ERp27 indicate extensive interdomain flexibility
ERp27 (endoplasmic reticulum protein 27.7 kDa) is a homologue of PDI (protein disulfide-isomerase) localized to the endoplasmic reticulum. ERp27 is predicted to consist of two thioredoxinfold domains homologous with the non-catalytic b and b domains of PDI. The structure in solution of the N-terminal blike domain of ERp27 was solved using high-resolution NMR data. The structure confirms that it has the thioredoxin fold and that ERp27 is a member of the PDI family. 15N-NMR relaxation data were obtained and ModelFree analysis highlighted limited exchange contributions and slow internal motions, and
indicated that the domain has an average order parameter S 2 of 0.79. Comparison of the single-domain structure determined in the present study with the equivalent domain within fulllength ERp27, determined independently by X-ray diffraction, indicated very close agreement. The domain interface inferred from NMR data in solution was much more extensive than that observed in the X-ray structure, suggesting that the domains flex independently and that crystallization selects one specific
interdomain orientation. This led us to apply a new rapid method to simulate the flexibility of the full-length protein, establishing that the domains show considerable freedom to flex (tilt and twist) about the interdomain linker, consistent with the NMR data
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
Buried and accessible surface area control intrinsic protein flexibility
Proteins experience a wide variety of conformational dynamics that can be
crucial for facilitating their diverse functions. How is the intrinsic
flexibility required for these motions encoded in their three-dimensional
structures? Here, the overall flexibility of a protein is demonstrated to be
tightly coupled to the total amount of surface area buried within its fold. A
simple proxy for this, the relative solvent accessible surface area (Arel),
therefore shows excellent agreement with independent measures of global protein
flexibility derived from various experimental and computational methods.
Application of Arel on a large scale demonstrates its utility by revealing
unique sequence and structural properties associated with intrinsic
flexibility. In particular, flexibility as measured by Arel shows little
correspondence with intrinsic disorder, but instead tends to be associated with
multiple domains and increased {\alpha}- helical structure. Furthermore, the
apparent flexibility of monomeric proteins is found to be useful for
identifying quaternary structure errors in published crystal structures. There
is also a strong tendency for the crystal structures of more flexible proteins
to be solved to lower resolutions. Finally, local solvent accessibility is
shown to be a primary determinant of local residue flexibility. Overall this
work provides both fundamental mechanistic insight into the origin of protein
flexibility and a simple, practical method for predicting flexibility from
protein structures.Comment: 36 pages, 11 figures, author's manuscript, accepted for publication
in Journal of Molecular Biolog
Elastic properties of proteins: insight on the folding process and evolutionary selection of native structures
We carry out a theoretical study of the vibrational and relaxation properties
of naturally-occurring proteins with the purpose of characterizing both the
folding and equilibrium thermodynamics. By means of a suitable model we provide
a full characterization of the spectrum and eigenmodes of vibration at various
temperatures by merely exploiting the knowledge of the protein native
structure. It is shown that the rate at which perturbations decay at the
folding transition correlates well with experimental folding rates. This
validation is carried out on a list of about 30 two-state folders. Furthermore,
the qualitative analysis of residues mean square displacements (shown to
accurately reproduce crystallographic data) provides a reliable and
statistically accurate method to identify crucial folding sites/contacts. This
novel strategy is validated against clinical data for HIV-1 Protease. Finally,
we compare the spectra and eigenmodes of vibration of natural proteins against
randomly-generated compact structures and regular random graphs. The comparison
reveals a distinctive enhanced flexibility of natural structures accompanied by
slow relaxation times at the folding temperature. The fact that these
properties are intimately connected to the presence and assembly of secondary
motifs hints at the special criteria adopted by evolution in the selection of
viable folds.Comment: Revtex 17 pages, 13 eps figure
On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm
N-Acetyl-L-Glutamate Kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence→structure→dynamics→function © 2010 Marcos et al
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