Minimal model for studying prion‐like folding pathways

Chen, Jeff Z. Y.; Lemak, Alexander; Lepock, James R.; Kemp, Josh

doi:10.1002/prot.10329

Cited by 10 publications

(14 citation statements)

References 24 publications

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“…The strengths of the hydrophobic contact, HP , considered in this article are 0, 1/12, 1/10, 1/8, 1/6, 1/4, and 1/2 the strength of a hydrogen bond, HB . Hydrogen bond strength and hydrophobic contact strength are independent of temperature, as has been assumed in previous simulation studies (Irback et al 2000;Smith and Hall 2001b,c;Chen et al 2003).…”

Section: Model Peptide and Forcesmentioning

confidence: 67%

Solvent effects on the conformational transition of a model polyalanine peptide

2004

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We have investigated the folding of polyalanine by combining discontinuous molecular dynamics simulation with our newly developed off-lattice intermediate-resolution protein model. The thermodynamics of a system containing a single Ac-KA 14 K-NH 2 molecule has been explored by using the replica exchange simulation method to map out the conformational transitions as a function of temperature. We have also explored the influence of solvent type on the folding process by varying the relative strength of the side-chain's hydrophobic interactions and backbone hydrogen bonding interactions. The peptide in our simulations tends to mimic real polyalanine in that it can exist in three distinct structural states: ␣-helix, ␤-structures (including ␤-hairpin and ␤-sheet-like structures), and random coil, depending upon the solvent conditions. At low values of the hydrophobic interaction strength between nonpolar side-chains, the polyalanine peptide undergoes a relatively sharp transition between an ␣-helical conformation at low temperatures and a random-coil conformation at high temperatures. As the hydrophobic interaction strength increases, this transition shifts to higher temperatures. Increasing the hydrophobic interaction strength even further induces a second transition to a ␤-hairpin, resulting in an ␣-helical conformation at low temperatures, a ␤-hairpin at intermediate temperatures, and a random coil at high temperatures. At very high values of the hydrophobic interaction strength, polyalanines become ␤-hairpins and ␤-sheet-like structures at low temperatures and random coils at high temperatures. This study of the folding of a single polyalanine-based peptide sets the stage for a study of polyalanine aggregation in a forthcoming paper.Keywords: polyalanine; ␣-␤ transition; secondary structures; solvent conditions; discontinuous molecular dynamics Small peptides undergo a spontaneous reversible disorderto-order transition to a unique, three-dimensional equilibrium structure such as an ␣-helix or a ␤-structure when exposed to favorable physiological conditions. The information necessary to drive this folding transition is universally accepted to be encrypted solely within the linear amino acid sequence (Anfinsen 1973;Anfinsen and Scheraga 1975). However, experiments indicate that many peptides can be folded into alternative stable structures by changing the solution conditions (Rosenheck and Doty 1961;Kabsch and Sander 1984;Mutter and Hersperger 1990;Mutter et al. 1991;Zhong and Johnson 1992;Cohen et al. 1993;Waterhous and Johnson 1994). For example, many peptides are well known to undergo a sharp helix-coil transition as the temperature is increased (Poland and Scheraga 1970;Rohl and Baldwin 1998). Furthermore, the conformational transition between the ␣-helix and ␤-structure is greatly influenced by solvent conditions, including the pH (Mutter and Hersperger 1990;Cerpa et al. 1996;Tuchscherer et al. 1999), the temperature (Cerpa et al. 1996;Fukushima 1996;Zhang and Rich 1997), the salt or organic cosolvent ...

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Section: Model Peptide and Forcesmentioning

confidence: 67%

Solvent effects on the conformational transition of a model polyalanine peptide

2004

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“…Recent computer simulations have been performed to address issues related to β‐hairpin folding based on two categories of models: all‐atom28–37 and minimal models 7, 27, 38–45. All‐atom models have been used to directly generate the microscopic folding trajectories of a β‐hairpin—mostly for the C‐terminal of protein GB1 in previous studies, in connection with experimental observations.…”

Section: Introductionmentioning

confidence: 99%

“…The approach taken in this work avoids such a potential pitfall. The current model is an extension to the previous work on characterizing the folding pathways for a prionlike model44, 45 and the structural conversion between the α‐helix and β‐hairpin due to mutation in a peptide sequence 45. In protein folding modeling, one of the major challenges is to find a single universal set of potential parameters for any protein conformations that can properly fold into a native conformation depending on only information encoded in the sequence,51 and our model meets this criterion.…”

Section: Introductionmentioning

confidence: 99%

Dependence of folding dynamics and structural stability on the location of a hydrophobic pair in β‐hairpins

Imamura

Chen

2006

Proteins

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We study the dependence of folding time, nucleation site, and stability of a model beta-hairpin on the location of a cross-strand hydrophobic pair, using a coarse-grained off-lattice model with the aid of Monte Carlo simulations. Our simulations have produced 6500 independent folding trajectories dynamically, forming the basis for extensive statistical analysis. Four folding pathways, zipping-out, middle-out, zipping-in, and reptation, have been closely monitored and discussed in all seven sequences studied. A hydrophobic pair placed near the beta-turn or in the middle section effectively speed up folding; a hydrophobic pair placed close to the terminal ends or next to the beta-turn encourages stability of the entire chain.

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“…The second model was developed by Chen and Imamura. 7,[22][23][24] It is based on a three bead per backbone residue model of a polymer and uses a special treatment for residues at the loops between secondary structure elements. The functional form of this model is distance but is not orientation-dependent.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of coarse grained models for hydrogen bonds in proteins

Sancho

Rey

2007

J Comput Chem

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Backbone hydrogen bonds contribute very importantly to the stability of proteins and therefore they must be appropriately represented in protein folding simulations. Simple models are frequently used in theoretical approaches to this process, but their simplifications are often confronted with the need to be true to the physics of the interactions. Here we study the effects of different levels of coarse graining in the modeling of backbone hydrogen bonds. We study three different models taken from the bibliography in a twofold fashion. First, we calculate the hydrogen bonds in 2gb1, an (alpha + beta)-protein, and see how different backbone representations and potentials can mimic the effects of real hydrogen bonds both in helices and sheets. Second, we use an evolutionary method for protein fragment assembly to locate the global energy minimum for a set of small beta-proteins with these models. This way, we assess the effects of coarse graining in hydrogen bonding models and show what can be expected from them when used in simulation experiments.

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Minimal model for studying prion‐like folding pathways

Cited by 10 publications

References 24 publications

Solvent effects on the conformational transition of a model polyalanine peptide

Solvent effects on the conformational transition of a model polyalanine peptide

Dependence of folding dynamics and structural stability on the location of a hydrophobic pair in β‐hairpins

Evaluation of coarse grained models for hydrogen bonds in proteins

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