Molecular dynamics and Monte Carlo simulations favor the .alpha.-helical form for alanine-based peptides in water

Tirado‐Rives, Julian; Maxwell, David S.; Jorgensen, William L.

doi:10.1021/ja00077a066

Cited by 103 publications

(129 citation statements)

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“…[27][28][29] Tobias and Brooks 17 obtained a helix = turn free energy of 1.4 kcal/mol for an alanine tetrapeptide in solution, with a barrier of about 2 kcal/mol, and a smaller barrier and a more stable turn for a valine tetrapeptide, consistent with the free energy magnitudes found here. Smythe et al 27 Fig.…”

Section: Discussionsupporting

confidence: 81%

“…TiradoRives et at. 29 observed ␣-helix = 3 10 transitions in Monte Carlo simulations of a small peptide.…”

Section: Discussionmentioning

confidence: 91%

“…A 3 10 -helical conformation is also sampled, as well as two other conformations, in which one or two of the helical hydrogen bonds are broken. 3 10 -helices have been proposed as possible intermediate structures in the initial unfolding stages of an ␣-helix, 19,28,29 and the conformations sampled here may be relevant to this process. Chemical shifts and NOE patterns were derived for each conformation and compared to experiment.…”

Section: Introductionmentioning

confidence: 91%

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Conformation of the Ras-binding domain of Raf studied by molecular dynamics and free energy simulations

Zeng¹,

Treutlein

Simonson³

1998

Proteins

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Recognition of Ras by its downstream target Raf is mediated by a Ras-recognition region in the Ras-binding domain (RBD) of Raf. Residues 78-89 in this region occupy two different conformations in the ensemble of NMR solution structures of the RBD: a fully alpha-helical one, and one where 87-90 form a type IV beta-turn. Molecular dynamics simulations of the RBD in solution were performed to explore the stability of these and other possible conformations of both the wild-type RBD and the R89K mutant, which does not bind Ras. The simulations sample a fully helical conformation for residues 78-89 similar to the NMR helical structures, a conformation where 85-89 form a 3(10)-helical turn, and a conformation where 87-90 form a type I beta-turn, whose free energies are all within 0.3 kcal/mol of each other. NOE patterns and H(alpha) chemical shifts from the simulations are in reasonable agreement with experiment. The NMR turn structure is calculated to be 3 kcal/mol higher than the three above conformations. In a simulation with the same implicit solvent model used in the NMR structure generation, the turn conformation relaxes into the fully helical conformation, illustrating possible structural artifacts introduced by the implicit solvent model. With the Raf R89K mutant, simulations sample a fully helical and a turn conformation, the turn being 0.9 kcal/mol more stable. Thus, the mutation affects the population of RBD conformations, and this is expected to affect Ras binding. For example, if the fully helical conformation of residues 78-89 is required for binding, its free energy increase in R89K will increase the binding free energy by about 0.6 kcal/mol.

show abstract

Section: Discussionsupporting

confidence: 81%

“…TiradoRives et at. 29 observed ␣-helix = 3 10 transitions in Monte Carlo simulations of a small peptide.…”

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 91%

See 1 more Smart Citation

Conformation of the Ras-binding domain of Raf studied by molecular dynamics and free energy simulations

Zeng¹,

Treutlein

Simonson³

1998

Proteins

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“…A similar conclusion emerged from other experimental 92 and theoretical studies. [104][105][106] The exact role of 3 10 -helices in facilitating folding is not clear, but it may be important that the formation of a through-backbone hydrogen bond in this structure requires that two consecutive peptide bonds adopt appropriate (, ) angles, whereas three peptide bonds must have the correct conformation to form a hydrogen bond in an ␣-helix. Once a 3 10 -helix is formed, conversion to an ␣-helix should be highly facilitated, both kinetically and thermodynamically.…”

Section: Resultsmentioning

confidence: 99%

Early events in the folding of an amphipathic peptide: A multinanosecond molecular dynamics study

1999

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“…A number of computer simulations have addressed the (~/3~,,/ coil equilibrium, both in AIB-rich peptides (Smythe et al, 1993;Basu et al, 1994;Huston & Marshall, 1994;Zhang & Hermans, 1994), and in proteins and peptides with no AIB residues (Soman et al, 1991;Tirado-Rives & Jorgensen, 1991;Tirado-Rives et al, 1993). Some of these studies suggest that the 3,,,-helix is a kinetic intermediate along the a-helix unfolding pathway (Soman et al, 1991;Tirado-Rives & Jorgensen, 1991;Tobias & Brooks, 1991).…”

mentioning

confidence: 99%

Addition of side‐chain interactions to 3₁₀‐helix/coil and α‐helix/3₁₀‐helix/coil theory

Sun

Doig

1998

Protein Science

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An increasing number of experimental and theoretical studies have demonstrated the importance of the 310-helix/ a-helix/coil equilibrium for the structure and folding of peptides and proteins. One way to perturb this equilibrium is to introduce side-chain interactions that stabilize or destabilize one helix. For example, an attractive i, i + 4 interaction, present only in the a-helix, will favor the a-helix over 310, while an i, i + 4 repulsion will favor the 310-helix over a.To quantify the 310/a/coil equilibrium, it is essential to use a helix/coil theory that considers the stability of every possible conformation of a peptide. We have previously developed models for the 310-helix/coil and 310-helix/a-helix/ coil equilibria. Here we extend this work by adding i, i + 3 and i, i + 4 side-chain interaction energies to the models.The theory is based on classifying residues into a-helical, 310-helical, or nonhelical (coil) conformations. Statistical weights are assigned to residues in a helical conformation with an associated helical hydrogen bond, a helical conformation with no hydrogen bond, an N-cap position, a C-cap position, or the reference coil conformation plus i, i + 3 and i, i + 4 side-chain interactions. This work may provide a framework for quantitatively rationalizing experimental work on isolated 310-helices and mixed 310-/a-helices and for predicting the locations and stabilities of these structures in peptides and proteins. We conclude that strong i, i + 4 side-chain interactions favor a-helix formation, while the 310-helix population is maximized when weaker i, i + 4 side-chain interactions are present.

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Molecular dynamics and Monte Carlo simulations favor the .alpha.-helical form for alanine-based peptides in water

Cited by 103 publications

References 0 publications

Conformation of the Ras-binding domain of Raf studied by molecular dynamics and free energy simulations

Conformation of the Ras-binding domain of Raf studied by molecular dynamics and free energy simulations

Early events in the folding of an amphipathic peptide: A multinanosecond molecular dynamics study

Addition of side‐chain interactions to 3₁₀‐helix/coil and α‐helix/3₁₀‐helix/coil theory

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Molecular dynamics and Monte Carlo simulations favor the .alpha.-helical form for alanine-based peptides in water

Cited by 103 publications

References 0 publications

Conformation of the Ras-binding domain of Raf studied by molecular dynamics and free energy simulations

Conformation of the Ras-binding domain of Raf studied by molecular dynamics and free energy simulations

Early events in the folding of an amphipathic peptide: A multinanosecond molecular dynamics study

Addition of side‐chain interactions to 310‐helix/coil and α‐helix/310‐helix/coil theory

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Addition of side‐chain interactions to 3₁₀‐helix/coil and α‐helix/3₁₀‐helix/coil theory