1,373 research outputs found
Design of Sequences with Good Folding Properties in Coarse-Grained Protein Models
Background: Designing amino acid sequences that are stable in a given target
structure amounts to maximizing a conditional probability. A straightforward
approach to accomplish this is a nested Monte Carlo where the conformation
space is explored over and over again for different fixed sequences, which
requires excessive computational demand. Several approximate attempts to remedy
this situation, based on energy minimization for fixed structure or high-
expansions, have been proposed. These methods are fast but often not accurate
since folding occurs at low .
Results: We develop a multisequence Monte Carlo procedure, where both
sequence and conformation space are simultaneously probed with efficient
prescriptions for pruning sequence space. The method is explored on
hydrophobic/polar models. We first discuss short lattice chains, in order to
compare with exact data and with other methods. The method is then successfully
applied to lattice chains with up to 50 monomers, and to off-lattice 20-mers.
Conclusions: The multisequence Monte Carlo method offers a new approach to
sequence design in coarse-grained models. It is much more efficient than
previous Monte Carlo methods, and is, as it stands, applicable to a fairly wide
range of two-letter models.Comment: 23 pages, 7 figure
Statics, metastable states and barriers in protein folding: A replica variational approach
Protein folding is analyzed using a replica variational formalism to
investigate some free energy landscape characteristics relevant for dynamics. A
random contact interaction model that satisfies the minimum frustration
principle is used to describe the coil-globule transition (characterized by
T_CG), glass transitions (by T_A and T_K) and folding transition (by T_F).
Trapping on the free energy landscape is characterized by two characteristic
temperatures, one dynamic, T_A the other static, T_K (T_A> T_K), which are
similar to those found in mean field theories of the Potts glass. 1)Above T_A,
the free energy landscape is monotonous and polymer is melted both dynamically
and statically. 2)Between T_A and T_K, the melted phase is still dominant
thermodynamically, but frozen metastable states, exponentially large in number,
appear. 3)A few lowest minima become thermodynamically dominant below T_K,
where the polymer is totally frozen. In the temperature range between T_A and
T_K, barriers between metastable states are shown to grow with decreasing
temperature suggesting super-Arrhenius behavior in a sufficiently large system.
Due to evolutionary constraints on fast folding, the folding temperature T_F is
expected to be higher than T_K, but may or may not be higher than T_A. Diverse
scenarios of the folding kinetics are discussed based on phase diagrams that
take into account the dynamical transition, as well as the static ones.Comment: 41 pages, LaTeX, 9 EPS figure
Single-domain protein folding: a multi-faceted problem
We review theoretical approaches, experiments and numerical simulations that
have been recently proposed to investigate the folding problem in single-domain
proteins. From a theoretical point of view, we emphasize the energy landscape
approach. As far as experiments are concerned, we focus on the recent
development of single-molecule techniques. In particular, we compare the
results obtained with two main techniques: single protein force measurements
with optical tweezers and single-molecule fluorescence in studies on the same
protein (RNase H). This allows us to point out some controversial issues such
as the nature of the denatured and intermediate states and possible folding
pathways. After reviewing the various numerical simulation techniques, we show
that on-lattice protein-like models can help to understand many controversial
issues.Comment: 26 pages, AIP Conference Proceeding
A graph theoretical analysis of the energy landscape of model polymers
In systems characterized by a rough potential energy landscape, local
energetic minima and saddles define a network of metastable states whose
topology strongly influences the dynamics. Changes in temperature, causing the
merging and splitting of metastable states, have non trivial effects on such
networks and must be taken into account. We do this by means of a recently
proposed renormalization procedure. This method is applied to analyze the
topology of the network of metastable states for different polypeptidic
sequences in a minimalistic polymer model. A smaller spectral dimension emerges
as a hallmark of stability of the global energy minimum and highlights a
non-obvious link between dynamic and thermodynamic properties.Comment: 15 pages, 15 figure
Protein Structure Prediction Using Basin-Hopping
Associative memory Hamiltonian structure prediction potentials are not overly
rugged, thereby suggesting their landscapes are like those of actual proteins.
In the present contribution we show how basin-hopping global optimization can
identify low-lying minima for the corresponding mildly frustrated energy
landscapes. For small systems the basin-hopping algorithm succeeds in locating
both lower minima and conformations closer to the experimental structure than
does molecular dynamics with simulated annealing. For large systems the
efficiency of basin-hopping decreases for our initial implementation, where the
steps consist of random perturbations to the Cartesian coordinates. We
implemented umbrella sampling using basin-hopping to further confirm when the
global minima are reached. We have also improved the energy surface by
employing bioinformatic techniques for reducing the roughness or variance of
the energy surface. Finally, the basin-hopping calculations have guided
improvements in the excluded volume of the Hamiltonian, producing better
structures. These results suggest a novel and transferable optimization scheme
for future energy function development
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