Computer simulation of the competition between protein folding and aggregation

Gupta, Prashant; Hall, Carol K.; Voegler, Anne C.

doi:10.1016/s0378-3812(99)00119-3

Cited by 32 publications

(26 citation statements)

References 15 publications

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“…They performed dynamic Monte Carlo simulations on a very simple two-dimensional HP lattice model of proteins (Gupta and Hall, 1995) to investigate the effect of solvent conditions (denaturant concentration and the protein concentration) on refolding and aggregation. They found that there were optimum levels of denaturant at which the refolding yield is highest, in agreement with some experimental observations (Gupta et al, 1998(Gupta et al, , 1999. Although Gupta and Hall simulated their systems for long periods of time, on the order of several trillion attempted moves, their runs were not long enough, in our opinion, to reach equilibrium.…”

Section: Introductionsupporting

confidence: 74%

Effect of rate of chemical or thermal renaturation on refolding and aggregation of a simple lattice protein

Nguyen

Hall

2002

Biotech & Bioengineering

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We used dynamic Monte Carlo simulation to investigate how changing the rate of chemical or thermal renaturation affects the folding and aggregation behavior of a system of simple, two-dimensional lattice protein molecules. Four renaturation methods were simulated: infinitely slow cooling; slow but finite cooling; quenching; and pulse renaturation. The infinitely slow cooling method, which is equivalent to dialysis or diafiltration, provides refolding yields that are relatively high and aggregates that are relatively small (mostly dimers or trimers). The slow but finite cooling method, which is equivalent to multiple-step dilution, provides refolding yields that are almost as high as those observed in the infinitely slow cooling case, but in a relatively short period of time. Quenching, which is equivalent to one-step dilution or quick quenching, is extremely slow and has low re- folding yields. A maximum appears in the refolding yield as a function of denaturant concentration in the simulation but disappears after a very long duration. Finally, the pulse renaturation method provides refolding yields that are substantially higher than those observed in the other three methods, even at high packing fractions. As in the early stages of quenching, there is a maximum in the refolding yield as a function of denaturant concentration when relatively large numbers of denatured chains are added to the refolding solution at each step.

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Section: Introductionsupporting

confidence: 74%

Effect of rate of chemical or thermal renaturation on refolding and aggregation of a simple lattice protein

Nguyen

Hall

2002

Biotech & Bioengineering

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“…This observation is in agreement with previous observations on a two-dimensional model system. 29 Moreover, as the transition between the coil and the native state of isolated proteins occurs for ⑀/k b TϭϪ1.73, the liquid phase stabilizes some conformations partially folded that would not be stable for an isolated chain. The effect of density on folding is even more striking in the solid.…”

Section: Discussionmentioning

confidence: 99%

Phase behavior of a lattice protein model

Combe

Frenkel

2003

The Journal of Chemical Physics

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We present a numerical simulation of the phase behavior of a simple model for a protein solution. We find that this system can occur in three phases, namely a dilute liquid, a dense liquid and a crystal. The transition from dilute-liquid to dense-liquid takes place in the regime where the fluid phase is metastable with respect to the crystal. We have computed the relative stabilities of different crystal morphologies. In addition, we have analyzed the ''nucleation'' of the native state of an isolated lattice protein. Using a ''Gō'' model ͓N. Gō, J. Stat. Phys. 30, 413 ͑1983͔͒ to describe the protein, we show that a first order transition exists between the native and the coil state. We show this by analyzing the free energy barrier for the coil-to-native transition.

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“…Given current computational capabilities, simpler models are required to simulate multiprotein systems. Computer simulations using low-resolution models, which are based on a coarse-grained representation of protein geometry and energetics, have been used by a few investigators to study protein aggregation [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] Although such models provide invaluable insights into the basic physics underlying protein aggregation in general, they do not adequately account for the different forces, such as hydrogen bonding, that play an important role in fibril formation.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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Fibrillary protein aggregates rich in β-sheet structure have been implicated in the pathology of several neurodegenerative diseases. In this work, we investigate the formation of fibrils by performing discontinuous molecular dynamics simulations on systems containing 12 to 96 model Ac-KA 14 K-NH 2 peptides using our newly-developed off-lattice, implicit-solvent, intermediateresolution model, PRIME. We find that at a low concentration, random-coil peptides assemble into α-helices at low temperatures. At intermediate concentrations, random-coil peptides assemble into α-helices at low temperatures and large β-sheet structures at high temperatures. At high concentrations, the system forms β-sheets over a wide range of temperatures. These assemble into fibrils above a critical temperature which decreases with concentration and exceeds the isolated peptide's folding temperature. At very high temperatures and all concentrations, the system is in a random-coil state. All of these results are in good qualitative agreement with those by Blondelle and coworkers on Ac-KA 14 K-NH 2 peptides. The fibrils observed in our simulations mimic the structural characteristics observed in experiments in terms of the number of sheets formed, the values of the intra-and inter-sheet separations, and the parallel peptide arrangement within each β-sheet. Finally, we find that when the strength of the hydrophobic interaction between non-polar sidechains is high compared to the strength of hydrogen bonding, amorphous aggregates, rather than fibrillar aggregates, are formed.

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Computer simulation of the competition between protein folding and aggregation

Cited by 32 publications

References 15 publications

Effect of rate of chemical or thermal renaturation on refolding and aggregation of a simple lattice protein

Effect of rate of chemical or thermal renaturation on refolding and aggregation of a simple lattice protein

Phase behavior of a lattice protein model

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

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