A multifunnel energy landscape encodes the competing α-helix and β-hairpin conformations for a designed peptide

Chakraborty, Debayan; Chebaro, Yassmine; Wales, David J.

doi:10.1039/c9cp04778f

Cited by 10 publications

(13 citation statements)

References 97 publications

(123 reference statements)

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“…4a). The helix-to-hairpin transition of CDC transmembrane residues is likely to occur via several intermediate structural states 24 with different local energy minima, including collapsed coil-like intermediates 25 . The transient states of the h-helix may contribute to disruptive forces that prime the membrane for hairpin insertion and to the displacement of lipids by water molecules at the inner hydrophilic surface of the pore, as observed by molecular dynamics simulations 26 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis for tuning activity and membrane specificity of bacterial cytolysins

et al. 2020

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Cholesterol-dependent cytolysins (CDCs) are pore-forming proteins that serve as major virulence factors for pathogenic bacteria. They target eukaryotic cells using different mechanisms, but all require the presence of cholesterol to pierce lipid bilayers. How CDCs use cholesterol to selectively lyse cells is essential for understanding virulence strategies of several pathogenic bacteria, and for repurposing CDCs to kill new cellular targets. Here we address that question by trapping an early state of pore formation for the CDC intermedilysin, bound to the human immune receptor CD59 in a nanodisc model membrane. Our cryo electron microscopy map reveals structural transitions required for oligomerization, which include the lateral movement of a key amphipathic helix. We demonstrate that the charge of this helix is crucial for tuning lytic activity of CDCs. Furthermore, we discover modifications that overcome the requirement of cholesterol for membrane rupture, which may facilitate engineering the target-cell specificity of pore-forming proteins.

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Section: Discussionmentioning

confidence: 99%

Structural basis for tuning activity and membrane specificity of bacterial cytolysins

et al. 2020

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“…Such a mechanism of b-sheet formation has been reported for other molecules, such as a designed peptide that forms a-helix and b-hairpin in equal proportions [89][90][91][92] . This peptide was designed by adding seven residues to a fully helical peptide 89 .…”

Section: Resultsmentioning

confidence: 69%

“…The region consisting of the additional seven residues was hydrophobic and formed an extended structure. As the extended region approaches the helix region, the hairpin is formed when the helix region forms the extended structure [90][91][92] . Consequently, this designed peptide can have both a-helix and b-hairpin.…”

Section: Resultsmentioning

confidence: 99%

Key residue for aggregation of amyloid-β peptides

Itoh

Yagi-Utsumi

Kato

et al. 2022

Preprint

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Amyloid-b peptides (Abs) are associated with Alzheimer’s disease and have two isoforms: Ab40 and Ab42. Although the difference between Ab40 and Ab42 is only two additional C-terminal residues, Ab42 aggregates much faster and is more toxic than Ab40. It is unknown what role the C-terminal two residues play in accelerating aggregation. Clarifying the differences between the oligomerization processes of Ab40 and Ab42 is essential to elucidate the key factors of oligomerization. Performing Hamiltonian replica-permutation molecular dynamics simulations for Ab40 and Ab42 to investigate the early oligomerization process, we identified the key residue, Arg5, for the Ab42 dimerization. The two additional residues in Ab42 allow the C-terminus to form contact with Arg5, and this contact stabilizes the b-hairpin. This b-hairpin promotes the intermolecular b-bridge formation. We also conducted experiments on Ab aggregations to validate these simulation results and confirmed that mutations of Arg5 remarkably suppressed the Ab42 aggregation.

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“…We now consider applications to multifunnel landscapes for an atomic cluster, a designed bistable peptide, and an RNA switch. Full details of how these databases were created are available in previous work; ,, here we show that an analysis of the first passage time distribution and the observation time scale provides new insight into the dynamics, with a direct connection to the underlying energy landscape.…”

Section: Analysis Of the First Passage Time Distributionmentioning

confidence: 81%

Dynamical Signatures of Multifunnel Energy Landscapes

Wales

2022

J. Phys. Chem. Lett.

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Multifunctional systems, such as molecular switches, exhibit multifunnel energy landscapes associated with the alternative functional states. In this contribution the multifunnel organization is decoded from dynamical signatures in the first passage time distribution between reactants and products. Characteristic relaxation rates are revealed by analyzing the kinetics as a function of the observation time scale, which scans the underlying distribution. Extracting the corresponding dynamical signatures provides direct insight into the organization of the molecular energy landscape, which will facilitate a rational design of target functionality. Examples are illustrated for multifunnel landscapes in biomolecular systems and an atomic cluster.

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A multifunnel energy landscape encodes the competing α-helix and β-hairpin conformations for a designed peptide

Abstract: The propensities to form different secondary structures are encoded in the multifunnel nature of the underlying free energy landscape, and conformational switching between such structures is a key element of protein folding and aggregation.

Cited by 10 publications

References 97 publications

Structural basis for tuning activity and membrane specificity of bacterial cytolysins

Structural basis for tuning activity and membrane specificity of bacterial cytolysins

Key residue for aggregation of amyloid-β peptides

Dynamical Signatures of Multifunnel Energy Landscapes

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