721 research outputs found
Optimal prediction of folding rates and transition state placement from native state geometry
A variety of experimental and theoretical studies have established that the
folding process of monomeric proteins is strongly influenced by the topology of
the native state. In particular, folding times have been shown to correlate
well with the contact order, a measure of contact locality. Our investigation
focuses on identifying additional topologic properties that correlate with
experimentally measurable quantities, such as folding rates and transition
state placement, for both two- and three-state folders. The validation against
data from forty experiments shows that a particular topologic property which
measures the interdepedence of contacts, termed cliquishness or clustering
coefficient, can account with significant accuracy both for the transition
state placement and especially for folding rates, the linear correlation
coefficient being . This result can be further improved to , by
optimally combining the distinct topologic information captured by cliquishness
and contact order.Comment: Revtex, 15 pages, 8 figure
Probing the entanglement and locating knots in ring polymers: a comparative study of different arc closure schemes
The interplay between the topological and geometrical properties of a polymer
ring can be clarified by establishing the entanglement trapped in any portion
(arc) of the ring. The task requires to close the open arcs into a ring, and
the resulting topological state may depend on the specific closure scheme that
is followed. To understand the impact of this ambiguity in contexts of
practical interest, such as knot localization in a ring with non trivial
topology, we apply various closure schemes to model ring polymers. The rings
have the same length and topological state (a trefoil knot) but have different
degree of compactness. The comparison suggests that a novel method, termed the
minimally-interfering closure, can be profitably used to characterize the arc
entanglement in a robust and computationally-efficient way. This closure method
is finally applied to the knot localization problem which is tackled using two
different localization schemes based on top-down or bottom-up searches.Comment: 9 pages, 7 figures. Submitted to Progress of Theoretical Physic
Accurate and efficient description of protein vibrational dynamics: comparing molecular dynamics and Gaussian models
Current all-atom potential based molecular dynamics (MD) allow the
identification of a protein's functional motions on a wide-range of
time-scales, up to few tens of ns. However, functional large scale motions of
proteins may occur on a time-scale currently not accessible by all-atom
potential based molecular dynamics. To avoid the massive computational effort
required by this approach several simplified schemes have been introduced. One
of the most satisfactory is the Gaussian Network approach based on the energy
expansion in terms of the deviation of the protein backbone from its native
configuration. Here we consider an extension of this model which captures in a
more realistic way the distribution of native interactions due to the
introduction of effective sidechain centroids. Since their location is entirely
determined by the protein backbone, the model is amenable to the same exact and
computationally efficient treatment as previous simpler models. The ability of
the model to describe the correlated motion of protein residues in
thermodynamic equilibrium is established through a series of successful
comparisons with an extensive (14 ns) MD simulation based on the AMBER
potential of HIV-1 protease in complex with a peptide substrate. Thus, the
model presented here emerges as a powerful tool to provide preliminary, fast
yet accurate characterizations of proteins near-native motion.Comment: 14 pages 7 figure
Recurrent oligomers in proteins - an optimal scheme reconciling accurate and concise backbone representations in automated folding and design studies
A novel scheme is introduced to capture the spatial correlations of
consecutive amino acids in naturally occurring proteins. This knowledge-based
strategy is able to carry out optimally automated subdivisions of protein
fragments into classes of similarity. The goal is to provide the minimal set of
protein oligomers (termed ``oligons'' for brevity) that is able to represent
any other fragment. At variance with previous studies where recurrent local
motifs were classified, our concern is to provide simplified protein
representations that have been optimised for use in automated folding and/or
design attempts. In such contexts it is paramount to limit the number of
degrees of freedom per amino acid without incurring in loss of accuracy of
structural representations. The suggested method finds, by construction, the
optimal compromise between these needs. Several possible oligon lengths are
considered. It is shown that meaningful classifications cannot be done for
lengths greater than 6 or smaller than 4. Different contexts are considered
were oligons of length 5 or 6 are recommendable. With only a few dozen of
oligons of such length, virtually any protein can be reproduced within typical
experimental uncertainties. Structural data for the oligons is made publicly
available.Comment: 19 pages, 13 postscript figure
Convergent dynamics in the protease enzymatic superfamily
Proteases regulate various aspects of the life cycle in all organisms by
cleaving specific peptide bonds. Their action is so central for biochemical
processes that at least 2% of any known genome encodes for proteolytic enzymes.
Here we show that selected proteases pairs, despite differences in oligomeric
state, catalytic residues and fold, share a common structural organization of
functionally relevant regions which are further shown to undergo similar
concerted movements. The structural and dynamical similarities found
pervasively across evolutionarily distant clans point to common mechanisms for
peptide hydrolysis.Comment: 13 pages, 6 figure
Molecular Dynamics Studies on HIV-1 Protease: Drug Resistance and Folding Pathways
Drug resistance to HIV-1 Protease involves accumulation of multiple mutations
in the protein. Here we investigate the role of these mutations by using
molecular dynamics simulations which exploit the influence of the native-state
topology in the folding process. Our calculations show that sites contributing
to phenotypic resistance of FDA-approved drugs are among the most sensitive
positions for the stability of partially folded states and should play a
relevant role in the folding process. Furthermore, associations between amino
acid sites mutating under drug treatment are shown to be statistically
correlated. The striking correlation between clinical data and our calculations
suggest a novel approach to the design of drugs tailored to bind regions
crucial not only for protein function but also for folding.Comment: Revtex, 14 pages, 7 eps figures. Proteins, Structure Function and
Genetics, in press (2001
Variational approach to protein design and extraction of interaction potentials
We present and discuss a novel approach to the direct and inverse protein
folding problem. The proposed strategy is based on a variational approach that
allows the simultaneous extraction of amino acid interactions and the
low-temperature free energy of sequences of amino acids. The knowledge-based
technique is simple and straightforward to implement even for realistic
off-lattice proteins because it does not entail threading-like procedures. Its
validity is assessed in the context of a lattice model by means of a variety of
stringent checks.Comment: 5 pages, 3 figure
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