Influence of the native topology on the folding barrier for small proteins

Prieto, Lidia; Rey, Antonio

doi:10.1063/1.2780154

Cited by 30 publications

(53 citation statements)

References 65 publications

(104 reference statements)

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“…Building upon this idea, the 40-residue helical protein BBL has been found to exhibit one-state folding thermodynamics according to a battery of quantitative experimental criteria: (i) probe-dependent equilibrium unfolding (12); (ii) complex coupling between denaturing agents (13); (iii) characteristic DSC thermogram (14); (iv) gradual melting of secondary structure (15); (v) heterogeneous atom-by-atom unfolding behaviors spanning the entire unfolding process (16); and (vi) generalized baseline crossings in fits to global two-state models (17). BBL equilibrium unfolding has also been investigated in molecular simulations, ranging from off-lattice models with Go potentials (18)(19)(20)(21)(22) to replica exchange molecular dynamics (REMD) simulations in explicit solvent (23,24). All simulations indicate that BBL crosses very minimal folding barriers, if any.…”

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confidence: 99%

Dynamics of one-state downhill protein folding

Oliva¹,

Naganathan²,

Muñoz³

2009

Proc. Natl. Acad. Sci. U.S.A.

106

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The small helical protein BBL has been shown to fold and unfold in the absence of a free energy barrier according to a battery of quantitative criteria in equilibrium experiments, including probedependent equilibrium unfolding, complex coupling between denaturing agents, characteristic DSC thermogram, gradual melting of secondary structure, and heterogeneous atom-by-atom unfolding behaviors spanning the entire unfolding process. Here, we present the results of nanosecond T-jump experiments probing backbone structure by IR and end-to-end distance by FRET. The folding dynamics observed with these two probes are both exponential with common relaxation times but have large differences in amplitude following their probe-dependent equilibrium unfolding. The quantitative analysis of amplitude and relaxation time data for both probes shows that BBL folding dynamics are fully consistent with the one-state folding scenario and incompatible with alternative models involving one or several barrier crossing events. At 333 K, the relaxation time for BBL is 1.3 s, in agreement with previous folding speed limit estimates. However, late folding events at room temperature are an order of magnitude slower (20 s), indicating a relatively rough underlying energy landscape. Our results in BBL expose the dynamic features of one-state folding and chart the intrinsic time-scales for conformational motions along the folding process. Interestingly, the simple self-averaging folding dynamics of BBL are the exact dynamic properties required in molecular rheostats, thus supporting a biological role for one-state folding.downhill folding ͉ folding landscape ͉ landscape topography ͉ protein dynamics T heory asserts that protein folding kinetics can be described as diffusion on a low dimensional free energy surface obtained by projecting the hyperdimensional energy landscapes of proteins into one or a few suitable order parameters (1, 2). The overall topography of such free energy surface and the conformational motions guiding folding are not resolvable by classical folding kinetics, but could be probed by time-resolved experiments of downhill folding (3). The difficulty resides in identifying examples of downhill folding relaxations. Stretched exponential decays and kinetic memory effects are not reliable signatures because they require the downhill free energy landscape to be rugged (4), and can also originate from other sources (5). Recently, downhill folding has been pursued by reengineering the fast-folding -repressor to accelerate folding with either mutations (6, 7) or stabilizing cosolvents (8). Approach to the barrierless regime was correlated with the emergence of an additional faster kinetic relaxation interpreted as the downhill decay from a vanishing barrier top (7). From these experiments, a folding speed limit of Ϸ2.5 s at 340 K was proposed for -repressor. This time-scale is close to the recent upper limit estimate of N/100 s (9) for -repressor [N ϭ 80] residues.A powerful alternative would be to measure conformational dynamics ...

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mentioning

confidence: 99%

Dynamics of one-state downhill protein folding

Oliva¹,

Naganathan²,

Muñoz³

2009

Proc. Natl. Acad. Sci. U.S.A.

106

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“…For residues with |i − j| ≥ 4, a native contact is considered when, in the protein conformation taken from the Protein Data Bank (PDB), 37 the shortest distance between any heavy atom belonging to either residue is less than 4.5 Å. In previous work from our group, where folding was studied at room pressure as a function of temperature alone, [38][39][40] a simple attractive potential with the mathematical form of a truncated harmonic well was defined for this interaction. Now, we are going to use a more complex potential, to include what has been called 29 an additional solvent separated minimum (ssm), and a desolvation barrier (db).…”

Section: A the Modelmentioning

confidence: 99%

“…[38][39][40]43 In every simulation, pressure has been kept "constant" (i.e., the value of ssm is not modified along every individual trajectory). The algorithm uses a parallel tempering simulation technique, 45 where several replicas of the system are simultaneously sampled at different temperatures, with occasional exchanges between replicas at contiguous temperatures.…”

Section: B Simulation Algorithmmentioning

confidence: 99%

Simulating protein unfolding under pressure with a coarse-grained model

Perezzan

Rey

2012

The Journal of Chemical Physics

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We describe and test a coarse-grained molecular model for the simulation of the effects of pressure on the folding/unfolding transition of proteins. The model is a structure-based one, which takes into account the desolvation barrier for the formation of the native contacts. The pressure is taken into account in a qualitative, mean field approach, acting on the parameters describing the native stabilizing interactions. The model has been tested by simulating the thermodynamic and structural behavior of protein GB1 with a parallel tempering Monte Carlo algorithm. At low effective pressures, the model reproduces the standard two-state thermal transition between the native and denatured states. However, at large pressures a new state appears. Its structural characteristics have been analyzed, showing that it corresponds to a swollen version of the native structure. This swollen state is at equilibrium with the native state at low temperatures, but gradually transforms into the thermally denatured state as temperature is increased. Therefore, our model predicts a downhill transition between the swollen and the denatured states. The analysis of the model permits us to obtain a phase diagram for the pressure-temperature behavior of the simulated system, which is compatible with the known elliptical shape of this diagram for real proteins.

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“…The standard characteristics of a replica exchange simulation methodology (number of temperatures and their values, frequency of replica exchange trials and their acceptance ratio, the proper travel of the replicas along the different temperatures, etc.) have been tested in our group for different interaction models of single and multiple chain systems in recent years, 30,[33][34][35] and they are also checked here to warrant a proper sampling, which allows for an accurate description of the equilibrium properties for the studied systems. Moreover, for each system, three or five independent REMC runs have been carried out, in order to provide statistically meaningful results.…”

Section: B Simulation Detailsmentioning

confidence: 99%

“…33,34 The interaction potential that we have used here is based on this off-lattice α-carbon representation and includes the two main driving forces in protein systems: hydrogen bonds and hydrophobic interactions. Detailed descriptions can be found in Refs.…”

Section: A System Description and Interaction Potentialmentioning

confidence: 99%

Sketching protein aggregation with a physics-based toy model

Enciso

Rey

2013

The Journal of Chemical Physics

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We explore the applicability of a single-bead coarse-grained molecular model to describe the competition between protein folding and aggregation. We have designed very simple and regular sequences, based on our previous studies on peptide aggregation, that successfully fold into the three main protein structural families (all-α, all-β, and α + β). Thanks to equilibrium computer simulations, we evaluate how temperature and concentration promote aggregation. Aggregates have been obtained for all the amino acid sequences considered, showing that this process is common to all proteins, as previously stated. However, each structural family presents particular characteristics that can be related to its specific balance between hydrogen bond and hydrophobic interactions. The model is very simple and has limitations, yet it is able to reproduce both the cooperative folding of isolated polypeptide chains with regular sequences and the formation of different types of aggregates at high concentrations. © 2013 AIP Publishing LLC. [http://dx

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Influence of the native topology on the folding barrier for small proteins

Cited by 30 publications

References 65 publications

Dynamics of one-state downhill protein folding

Dynamics of one-state downhill protein folding

Simulating protein unfolding under pressure with a coarse-grained model

Sketching protein aggregation with a physics-based toy model

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