Examination of the Folding of a Short Alanine-Based Helical Peptide with Salt Bridges Using Molecular Dynamics Simulation

Wang, Weizhou; Lin, Topp; Sun, Yu

doi:10.1021/jp067637a

Cited by 17 publications

(22 citation statements)

References 48 publications

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“…Our D(Q) variation comes out somewhat stronger than from similar simulations with implicit solvent, suggesting that explicit solvent further increases the importance of diffusivity inhomogeneities [24]. In fact, to match experimental folding times of simple alpha-helix forming oligo-peptides within solvent-implicit simulations, an overall correction factor to the time scales is typically applied [47,48]. A detailed microsopic justification for this is lacking; on the contrary, it has been shown that in many cases explicit solvent strongly influences the free energy landscape and introduces novel kinetic mechanisms that are completely absent in solvent-implicit simulations [49,50].…”

Section: Discussionmentioning

confidence: 81%

How the diffusivity profile reduces the arbitrariness of protein folding free energies

Hinczewski

Hansen²,

Dzubiella³

et al. 2010

The Journal of Chemical Physics

134

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The concept of a protein diffusing in its free energy folding landscape has been fruitful for both theory and experiment. Yet the choice of the reaction coordinate (RC) introduces an undesirable degree of arbitrariness into the problem. We analyze extensive simulation data of an α-helix in explicit water solvent as it stochastically folds and unfolds. The free energy profiles for different RCs exhibit significant variation, some having an activation barrier, others not. We show that this variation has little effect on the predicted folding kinetics if the diffusivity profiles are properly taken into account. This kinetic quasi-universality is rationalized by an RC rescaling, which, due to the reparameterization invariance of the Fokker-Planck equation, allows the combination of free energy and diffusivity effects into a single function, the rescaled free energy profile. This rescaled free energy indeed shows less variation among different RCs than the bare free energy and diffusivity profiles separately do, if we properly distinguish between RCs that contain knowledge of the native state and those that are purely geometric in nature. Our method for extracting diffusivity profiles is easily applied to experimental single molecule time series data and might help to reconcile conflicts that arise when comparing results from different experimental probes for the same protein.

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Section: Discussionmentioning

confidence: 81%

How the diffusivity profile reduces the arbitrariness of protein folding free energies

Hinczewski

Hansen²,

Dzubiella³

et al. 2010

The Journal of Chemical Physics

134

View full text Add to dashboard Cite

show abstract

“…The alteration of average helicity per residue as a function of time was illustrated in contour plots (see Figs. 2, 3), which type of representation was previously applied for an Ala-based peptide [45], while the final average helicities with regard to the amino acid residues of AK and AR peptides are shown in Table 1. The contour plot of all Alabased oligopeptides, as well as the final helicity values represented in Table 1, pointed out that the first few amino acids at the N-terminal end could be characterized by a larger average a-helical content than that observed for the last few residues at the C-terminal end.…”

Section: Helicity Evolutionsmentioning

confidence: 99%

Helix and H-bond formations of alanine-based peptides containing basic amino acids

et al. 2011

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We studied comprehensively the helicity and H-bonding evolutions during the folding processes of Lysand Arg-containing alanine-based peptides. The evolution of a-helical conformation concerning the entire sequence and each amino acid residue was examined, as well as the helix-forming propensities were characterized. The formation of various types of the intramolecular H-bonds was also investigated, pointing out the helix-stabilizing role of local interactions and the destabilizing role of non-local interplays. Our study led to the observation that the nonlocal H-bonds affected the evolution of helical conformations, as well as the entire folding processes.

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“…Molecular dynamics simulations provide an alternative approach to study the ability of a peptide to form stable helical structure and the advantage of this technique is that the details leading to helix folding/unwinding events of a peptide can be studied sequentially at atomic level. Previous simulation studies to investigate the secondary structure of a peptide have been carried out on alanine-based peptides [26,27], a prion peptide [28], amyloid b-peptide [29] and stapled p53 peptide analogs [30] in explicit solvent. Recently, a molecular dynamics simulation study on the solution conformation of 16-mer peptide belonging to the BH3 region of pro-apoptotic Bak protein showed the presence of substantially stable short helices [31].…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations of pro-apoptotic BH3 peptide helices in aqueous medium: relationship between helix stability and their binding affinities to the anti-apoptotic protein Bcl-XL

Sankararamakrishnan

2011

J Comput Aided Mol Des

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The B-cell lymphoma 2 (Bcl-2) family of proteins regulates the intrinsic pathway of apoptosis. Interactions between specific anti- and pro-apoptotic Bcl-2 proteins determine the fate of a cell. Anti-apoptotic Bcl-2 proteins have been shown to be over-expressed in certain cancers and they are attractive targets for developing anti-cancer drugs. Peptides from the BH3 region of pro-apoptotic proteins have been shown to interact with anti-apoptotic Bcl-2 proteins and induce biological activity similar to that observed in parent proteins. However, the specificity of BH3 peptides derived from different pro-apoptotic proteins differ for different anti-apoptotic Bcl-2 proteins. In this study, we have investigated the relationship between the stable helical nature of BH3 peptides and their affinities to Bcl-X(L), an anti-apoptotic Bcl-2 protein. We have carried out molecular dynamics simulations of six BH3 peptides derived from Bak, Bad and Bim pro-apoptotic proteins for a period of 50 ns each in aqueous medium. Due to the amphipathic nature of BH3 peptides, the hydrophobic residues on the hydrophobic face tend to cluster together in all BH3 peptides. While this process resulted in a complete loss of helical structure in 16-mer Bak and 16-mer Bad wild type peptides, stabilizing interactions in the hydrophilic face of the BH3 peptides and capping interactions helped to maintain partial helical character in 16-mer Bad mutant and 16-mer Bim peptides. The latter two 16-mer peptides exhibit higher affinity for Bcl-X(L). Similarly the longer BH3 peptides, 25-mer Bad and 33-mer Bim, also resulted in smaller and stable helical fragments and their helical conformation is stabilized by interactions between residues in the solvent-exposed hydrophilic half of the peptide. The stable nature of helical segment in a BH3 peptide can be directly correlated to its binding affinity and the helical region encompassed the highly conserved Leu residue. We propose that upon approaching the hydrophobic groove of anti-apoptotic proteins, a longer helix will be induced in high affinity BH3 peptides by extending the smaller stable helical segments around the conserved Leu residue in both N- and C-terminal regions. The results reported in this study will have implications in developing peptide-based inhibitors for anti-apoptotic Bcl-2 proteins.

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Examination of the Folding of a Short Alanine-Based Helical Peptide with Salt Bridges Using Molecular Dynamics Simulation

Cited by 17 publications

References 48 publications

How the diffusivity profile reduces the arbitrariness of protein folding free energies

How the diffusivity profile reduces the arbitrariness of protein folding free energies

Helix and H-bond formations of alanine-based peptides containing basic amino acids

Molecular dynamics simulations of pro-apoptotic BH3 peptide helices in aqueous medium: relationship between helix stability and their binding affinities to the anti-apoptotic protein Bcl-XL

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