A Molecular Dynamics Study of the Formation, Stability, and Oligomerization State of Two Designed Coiled Coils: Possibilities and Limitations

Piñeiro, Ángel; Villa, Alessandra; Vagt, Toni; Koksch, Beate; Mark, Alan E.

doi:10.1529/biophysj.104.055590

Cited by 26 publications

(22 citation statements)

References 60 publications

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“…The oligomerization state is an important structural parameter in the formation of coiled-coil assemblies that is not strictly predictable by the design. [61,62] Therefore, the oligomerization state of the inhibitor VW01 was experimentally determined by analytical ultracentrifugation (AUZ). We ran both sedimentation velocity (SV) and sedimentation equilibrium (SE) experiments.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Brandenburg

Berlepsch

Gerling

et al. 2011

Chemistry A European J

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The formation of amyloid aggregates is responsible for a wide range of diseases, including Alzheimer's and Parkinson's disease. Although the amyloid-forming proteins have different structures and sequences, all undergo a conformational change to form amyloid aggregates that have a characteristic cross-β-structure. The mechanistic details of this process are poorly understood, but different strategies for the development of inhibitors of amyloid formation have been proposed. In most cases, chemically diverse compounds bind to an elongated form of the protein in a β-strand conformation and thereby exert their therapeutic effect. However, this approach could favor the formation of prefibrillar oligomeric species, which are thought to be toxic. Herein, we report an alternative approach in which a helical coiled-coil-based inhibitor peptide has been designed to engage a coiled-coil-based amyloid-forming model peptide in a stable coiled-coil arrangement, thereby preventing rearrangement into a β-sheet conformation and the subsequent formation of amyloid-like fibrils. Moreover, we show that the helix-forming peptide is able to disassemble mature amyloid-like fibrils.

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Section: Wwwchemeurjorgmentioning

confidence: 99%

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Brandenburg

Berlepsch

Gerling

et al. 2011

Chemistry A European J

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“…From previous experimental (Kohn et al 1995;Yu et al 1996;Hendsch and Tidor 1999) and computational studies (Mohanty et al 1999;Missimer et al 2005;Pineiro et al 2005), we expect that the wild-type GCN4-LZ will be stable at both neutral and low pH. To address this, we performed simulations starting with the GCN4-LZ crystal structure immersed in a box of water molecules.…”

Section: Resultsmentioning

confidence: 99%

“…These mutation to the surface of cancer cells (Moll et al 2001). Coiled-coil proteins have been extensively investigated using various experimental techniques such as NMR (Nikolaev and Pervushin 2007), X-ray diffraction (O'Shea et al 1991), circular dichroism (CD) and fl uorescence spectroscopy (Suzuki et al 1998), differential scanning calorimetry (DSC) (Yu et al 1996) and electron spin resonance (ESR) spectroscopy (Columbus and Hubbell 2004) as well as theoretical and computational approaches using molecular dynamics (MD) simulation techniques (Mohanty et al 1999;Missimer et al 2005;Pineiro et al 2005). MD simulations provide a means to understand the structural and dynamic behavior of coiled-coil at the atomic level which is often inaccessible to experimental tools.…”

Section: Peptide Designmentioning

confidence: 99%

Reversible pH-controlled DNA-binding peptide nanotweezers: An in-silico study

Sharma

Rege²,

Budil

et al. 2008

IJN

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Abstract:We describe the molecular dynamics (MD)-aided engineering design of mutant peptides based on the α-helical coiled-coil GCN4 leucine zipper peptide (GCN4-p1) in order to obtain environmentally-responsive nanotweezers. The actuation mechanism of the nanotweezers depends on the modifi cation of electrostatic charges on the residues along the length of the coiled coil. Modulating the solution pH between neutral and acidic values results in the reversible movement of helices toward and away from each other and creates a complete closed-open-closed transition cycle between the helices. Our results indicate that the mutants show a reversible opening of up to 15 Å (1.5 nm; approximately 150% of the initial separation) upon pH actuation. Investigation on the physicochemical phenomena that infl uence conformational properties, structural stability, and reversibility of the coiled-coil peptide-based nanotweezers revealed that a rationale-and design-based approach is needed to engineer stable peptide or macromolecules into stimuli-responsive devices. The effi cacy of the mutant that demonstrated the most signifi cant reversible actuation for environmentally responsive modulation of DNA-binding activity was also demonstrated. Our results have signifi cant implications in bioseparations and in the engineering of novel transcription factors.

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“…Experimentally, the Klok group [62][63][64][65][66], the Kros group [67][68][69][70][71], and the Xu group [72][73][74][75][76] synthesized PEGylated coiled coils, characterized their conformation and structure, and investigated the effect of PEGylation on the self-assembled structures and the interactions with other molecules. Computationally, the sequenced-based programs were developed to predict the existence and structure of coiled coils [77][78][79][80][81][82][83], and MD simulations were performed to study the stability of coiled coils [84][85][86][87][88][89][90][91][92][93].…”

Section: Coiled-coil Peptidesmentioning

confidence: 99%

Molecular Modeling of PEGylated Peptides, Dendrimers, and Single-Walled Carbon Nanotubes for Biomedical Applications

Lee

2014

Polymers

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Polyethylene glycol (PEG) has been conjugated to many drugs or drug carriers to increase their solubility and circulating lifetime, and reduce toxicity. This has motivated many experimental studies to understand the effect of PEGylation on delivery efficiency. To complement the experimental findings and uncover the mechanism that cannot be captured by experiments, all-atom and coarse-grained molecular dynamics (MD) simulations have been performed. This has become possible, due to recent advances in simulation methodologies and computational power. Simulations of PEGylated peptides show that PEG chains wrap antimicrobial peptides and weaken their binding interactions with lipid bilayers. PEGylation also influences the helical stability and tertiary structure of coiled-coil peptides. PEGylated dendrimers and single-walled carbon nanotubes (SWNTs) were simulated, showing that the PEG size and grafting density significantly modulate the conformation and structure of the PEGylated complex, the interparticle aggregation, and the interaction with lipid bilayers. In particular, simulations predicted the structural transition between the dense core and dense shell of PEGylated dendrimers, the phase behavior of self-assembled complexes of lipids, PEGylated lipids, and SWNTs, which all favorably compared with experiments. Overall, these new findings indicate that simulations can now predict the experimentally observed structure and dynamics, as well as provide atomic-scale insights into the interactions of PEGylated complexes with other molecules.

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A Molecular Dynamics Study of the Formation, Stability, and Oligomerization State of Two Designed Coiled Coils: Possibilities and Limitations

Cited by 26 publications

References 60 publications

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Reversible pH-controlled DNA-binding peptide nanotweezers: An in-silico study

Molecular Modeling of PEGylated Peptides, Dendrimers, and Single-Walled Carbon Nanotubes for Biomedical Applications

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