Generalized–ensemble method study: A <scp>helix‐mimetic</scp> compound inhibits protein–protein interaction by <scp>long‐range</scp> and <scp>short‐range</scp> intermolecular interactions

Higo, Junichi; Takashima, Hajime; Fukunishi, Yoshifumi; Yoshimori, Atsushi

doi:10.1002/jcc.26516

Cited by 10 publications

(14 citation statements)

References 89 publications

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“…It also ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model . Detailed in silico analysis by enhanced molecular dynamics simulation revealed that this scaffold induced PPI inhibition by long-range molecular orientation ordering followed by short-range interactions …”

Section: Introductionmentioning

confidence: 98%

Visualized and Quantitative Conformational Analysis of Peptidomimetics

Takashima

Yoshimori²,

Honda

et al. 2021

ACS Omega

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Protein−protein interactions (PPIs) are fundamentally important and challenging drug targets. Peptidomimetic molecules of various types have been developed to modulate PPIs. A particularly promising drug discovery strategy, structural peptidomimetics, was designed based on special mimicking of sidechain C α −C β bonds. It is simple and versatile. Nevertheless, no quantitative method has been established to evaluate its similarity to a target peptide motif. We developed two methods that enable visual, comprehensive, and quantitative analysis of peptidomimetics: peptide conformation distribution (PCD) plot and peptidomimetic analysis (PMA) map. These methods specifically examine multiple side-chain C α −C β bonds of a peptide fragment motif and their corresponding bonds (pseudo-C α −C β bonds) in a mimetic molecule instead of φ and ψ angles of a single amino acid in the traditional Ramachandran plot. The PCD plot is an alignment-free method, whereas the PMA map is an alignment-based method providing distinctive and complementary analysis. Results obtained from analysis using these two methods indicate our multifacial α-helix mimetic scaffold 12 as an excellent peptidomimetic that can precisely mimic the spatial positioning of side-chain functional groups of α-helix. These methods are useful for visualized and quantified evaluation of peptidomimetics and for the rational design of new mimetic scaffolds.

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Section: Introductionmentioning

confidence: 98%

Visualized and Quantitative Conformational Analysis of Peptidomimetics

Takashima

Yoshimori²,

Honda

et al. 2021

ACS Omega

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“…First, we briefly explain this method, which provides a conformational ensemble of the system and a thermodynamic weight at the simulation temperature 𝑇 ( 300 K in the present study), which is assigned to conformations stored in the ensemble. Details of GA-mD-VcMD have been explained elsewhere 13,14,15,16 . Next, we explain the molecular system which consists of hETB, bosentan, membrane (cholesterol and POPC lipid molecules), and solvent (water molecules and ions).…”

Section: Methodsmentioning

confidence: 99%

“…We applied this method to some biological systems, which consist of a protein and ligand in an explicit solvent 14,15,16 .…”

Section: Introductionmentioning

confidence: 99%

Fly-Casting with Ligand–Sliding and Orientational Selection to Support the Complex Formation of a GPCR and a Middle-Sized Flexible Molecule

Higo

Kasahara

Bekker

et al. 2022

Preprint

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A GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was performed to elucidate a binding mechanism of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB). GA-mD-VcMD is one of generalized ensemble methods and produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stably keeping the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model, and sampling was carried out from conformations where bosentan was distant from the binding site in the hETB’s binding pocket. The deepest basin in the resultant free-energy landscape was assigned to the native-like complex conformation. The obtained binding mechanism is as follows. First, bosentan fluctuating randomly in solution is captured by a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly-casting). Bosentan then occasionally slides from the tip to root of the N-terminal tail (ligand–sliding). In this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with accompanying a quick reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand–receptor attractive native contacts are formed, and eventually the native-like complex is completed. The bosentan-captured conformations by the tip- and root-regions of the N-terminal tail correspond to two basins in the free-energy landscape, and the ligand–sliding corresponds to overcoming a free-energy barrier between the basins.

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Section: Methodsmentioning

confidence: 99%

“…To overcome this difficulty, we introduced a GA-guided multi-dimensional virtual-system coupled molecular dynamics method (GA-mD-VcMD) 13 , which is an extension of the original mD-VcMD, where "GA" is an abbreviation of genetic algorithm. We applied this method to some biological systems, which consist of a protein and ligand in an explicit solvent 14,15,16 .…”

Section: Introductionmentioning

confidence: 99%

Fly-casting with ligand–sliding and orientational selection to support the complex formation of a GPCR and a middle-sized flexible molecule

Higo

Kasahara

Bekker

et al. 2022

Preprint

Self Cite

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To elucidate computationally a binding mechanism of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB), a GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was performed. This method is one of generalized ensemble methods and produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stably keeping the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model, and sampling was carried out from conformations where bosentan was distant from the binding site in the hETB's binding pocket. The deepest basin in the resultant free-energy landscape was assigned to the native-like complex conformation. The obtained binding mechanism is as follows. First, bosentan fluctuating randomly in solution is captured by a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly-casting). Bosentan then occasionally slides from the tip to root of the N-terminal tail (ligand-sliding). In this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with accompanying a quick reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand-receptor attractive native contacts are formed, and eventually the native-like complex is completed. The bosentan-captured conformations by the tip- and root-regions of the N-terminal tail correspond to two basins in the free-energy landscape, and the ligand-sliding corresponds to overcoming a free-energy barrier between the basins.

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Generalized–ensemble method study: A helix‐mimetic compound inhibits protein–protein interaction by long‐range and short‐range intermolecular interactions

Cited by 10 publications

References 89 publications

Visualized and Quantitative Conformational Analysis of Peptidomimetics

Visualized and Quantitative Conformational Analysis of Peptidomimetics

Fly-Casting with Ligand–Sliding and Orientational Selection to Support the Complex Formation of a GPCR and a Middle-Sized Flexible Molecule

Fly-casting with ligand–sliding and orientational selection to support the complex formation of a GPCR and a middle-sized flexible molecule

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