Rational Design of the Minimal Requirement for Helix–Helix Peptide Interactions in the Trimer-of-Hairpins Motif of Pediatric Pneumonia RSV Fusion Glycoprotein

Bao, Daocheng; Bian, Hongliang; Xu, Darong; Zhao, Chunyang; Jin, Qinian; Zhu, Min; Tao, Tingting; Cai, Jinlan

doi:10.1007/s10989-018-9756-z

Cited by 7 publications

(4 citation statements)

References 38 publications

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“…S4). Both the magnitudes of these values and the fluctuations are well within the ranges reported in similar studies . From Δ G eff values alone, the 4/5 interface appears to be more favorable than the 1/8 interface.…”

Section: Resultssupporting

confidence: 86%

“…Both the magnitudes of these values and the fluctuations are well within the ranges reported in similar studies. [84][85][86] From ΔG eff values alone, the 4/5 interface appears to be more favorable than the 1/8 interface. Note, however, that we did not consider configurational entropy contributions in the MM-PBSA computations, in order to avoid introducing additional uncertainty in the computations.…”

Section: Constants and Free Energies Of Associationmentioning

confidence: 99%

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Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

et al. 2019

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We describe the first extensive energetic evaluation of GPCR dimerization on the atomistic level by means of potential of mean force (PMF) computations and implicit solvent/implicit membrane end‐point free energy calculations (MM‐PBSA approach). Free energies of association computed from the PMFs show that the formation of both the 1/8 and 4/5 interface is energetically favorable for TGR5, the first GPCR known to be activated by hydrophobic bile acids and neurosteroids. Furthermore, formation of the 1/8 interface is favored over that of the 4/5 interface. Both results are in line with our previous FRET experiments in live cells. Differences in lipid‐protein interactions are identified to contribute to the observed differences in free energies of association. A per‐residue decomposition of the MM‐PBSA effective binding energy reveals hot spot residues specific for both interfaces that form clusters. This knowledge may be used to guide the design of dimerization inhibitors or perform mutational studies to explore physiological consequences of distorted TGR5 association. Finally, we characterized the role of Y111, located in the conserved (D/E)RY motif, as a facilitator of TGR5 interactions. The types of computations performed here should be transferable to other transmembrane proteins that form dimers or higher oligomers as long as good structural models of the dimeric or oligomeric states are available. Such computations may help to overcome current restrictions due to an imperfect energetic representation of protein association at the coarse‐grained level. © 2019 Wiley Periodicals, Inc.

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Section: Resultssupporting

confidence: 86%

Section: Constants and Free Energies Of Associationmentioning

confidence: 99%

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

et al. 2019

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“…Bao et al. () also determined the core structural elements of RSV‐F TOH motif by computationally reducing and dissecting the protein crystal structure, and found that a helical dimer can be regarded as the building blocks of the motif.…”

Section: Introductionmentioning

confidence: 99%

“…Epitopefocused vaccine design (EFVD) technique has been successfully proposed by Correia, Bates, Loomis, Baneyx, & Carrico (2014) to elicit an engineered immunogen of RSV-F protein, which was further redesigned to obtain a series of prophylactic peptide vaccines against pediatric viral pneumonia (Ni, Zhuang, Chen, & Ji, 2018). Bao et al (2018) also determined the core structural elements of RSV-F TOH motif by computationally reducing and dissecting the protein crystal structure, and found that a helical dimer can be regarded as the building blocks of the motif.…”

Section: Introductionmentioning

confidence: 99%

Molecular design of sequence‐minimized, structure‐optimized, and hydrocarbon‐stapled helix–helix interactions in the trimer‐of‐hairpins motif of pediatric pneumonia RSV‐F protein

et al. 2019

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The respiratory syncytial virus fusion (RSV‐F) protein is a primary target for vaccine and drug development against respiratory infection and pediatric pneumonia. The RSV‐F core forms a trimer‐of‐hairpins (TOH) motif in postfusion conformation, which is characterized by a six‐helix bundle (6HB) where the three N‐terminal HRn helices define a central coiled‐coil, while three C‐terminal HRc helices pack on the coiled‐coil surface in an antiparallel manner. Here, one tightly packed HRn–HRc helix–helix interaction is stripped from the 6HB, which represents the minimum unit of RSV‐F TOH motif. The helix–helix interaction sequence can be truncated to derive a core binding region (CBR) that covers intense nonbonded interactions across the interaction interface. Dynamics simulation and energetics analysis reveal that the CBR HRc peptide has a large flexibility and intrinsic disorder in unbound free state, which would incur a considerable entropy penalty upon its binding to CBR NRn peptide. Two strategies are described to constrain the HRc peptide conformation. First, the four non‐interfacial residues of HRc peptide are artificially substituted with new amino acid combinations of high helical propensity and, second, the helical conformation of wild‐type and mutant HRc peptides is stabilized by adding an all‐hydrocarbon bridge across two spatially vicinal, non‐interfacial residues 503 (i) and 507 (i + 4). Free energy calculation and fluorescence‐based assay confirm that the substitution and stapling can effectively improve the binding affinity of CBR HRn–HRc interaction.

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Molecular Stapling of Human Pediatric RSV Phosphoprotein’s C-terminal Tail-Derived Peptides to Target the Coupled Folding-Upon-Binding Event Between Phosphoprotein and Nucleocapsid

Zhang

Gong

Shen

2022

Int J Pept Res Ther

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Rational Design of the Minimal Requirement for Helix–Helix Peptide Interactions in the Trimer-of-Hairpins Motif of Pediatric Pneumonia RSV Fusion Glycoprotein

Cited by 7 publications

References 38 publications

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

Molecular design of sequence‐minimized, structure‐optimized, and hydrocarbon‐stapled helix–helix interactions in the trimer‐of‐hairpins motif of pediatric pneumonia RSV‐F protein

Molecular Stapling of Human Pediatric RSV Phosphoprotein’s C-terminal Tail-Derived Peptides to Target the Coupled Folding-Upon-Binding Event Between Phosphoprotein and Nucleocapsid

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