A Free-Energy Landscape for Coupled Folding and Binding of an Intrinsically Disordered Protein in Explicit Solvent from Detailed All-Atom Computations

2011 ◽  
Vol 133 (27) ◽  
pp. 10448-10458 ◽  
Author(s):  
Junichi Higo ◽  
Yoshifumi Nishimura ◽  
Haruki Nakamura
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Intrinsically Disordered Protein ◽  
Free Energy Landscape ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Explicit Solvent

scholarly journals Free-energy landscape of molecular interactions between endothelin 1 and human endothelin type B receptor: fly-casting mechanism

2019 ◽  
Vol 32 (7) ◽  
pp. 297-308 ◽  
Author(s):  
Junichi Higo ◽  
Kota Kasahara ◽  
Mitsuhito Wada ◽  
Bhaskar Dasgupta ◽  
Narutoshi Kamiya ◽  
...  
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Binding Pocket ◽  
Free Energy Landscape ◽  
Type B ◽  
Endothelin 1 ◽  
Reaction Coordinates ◽  
Explicit Solvent ◽  
Virtual System ◽  
G Protein Coupled

Abstract The free-energy landscape of interaction between a medium-sized peptide, endothelin 1 (ET1), and its receptor, human endothelin type B receptor (hETB), was computed using multidimensional virtual-system coupled molecular dynamics, which controls the system’s motions by introducing multiple reaction coordinates. The hETB embedded in lipid bilayer was immersed in explicit solvent. All molecules were expressed as all-atom models. The resultant free-energy landscape had five ranges with decreasing ET1–hETB distance: completely dissociative, outside-gate, gate, binding pocket, and genuine-bound ranges. In the completely dissociative range, no ET1–hETB interaction appeared. In the outside-gate range, an ET1–hETB attractive interaction was the fly-casting mechanism. In the gate range, the ET1 orientational variety decreased rapidly. In the binding pocket range, ET1 was in a narrow pathway with a steep free-energy slope. In the genuine-bound range, ET1 was in a stable free-energy basin. A G-protein-coupled receptor (GPCR) might capture its ligand from a distant place.

scholarly journals Folding Free Energy Landscape of Ordered and Intrinsically Disordered Proteins

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Song-Ho Chong ◽  
Sihyun Ham
Keyword(s):  
Free Energy ◽  
Intrinsically Disordered Proteins ◽  
Energy Landscape ◽  
Disordered Proteins ◽  
Free Energy Landscape ◽  
Ww Domain ◽  
Intrinsically Disordered ◽  
Ca 50 ◽  
Folding Free Energy

Abstract Folding funnel is the essential concept of the free energy landscape for ordered proteins. How does this concept apply to intrinsically disordered proteins (IDPs)? Here, we address this fundamental question through the explicit characterization of the free energy landscapes of the representative α-helical (HP-35) and β-sheet (WW domain) proteins and of an IDP (pKID) that folds upon binding to its partner (KIX). We demonstrate that HP-35 and WW domain indeed exhibit the steep folding funnel: the landscape slope for these proteins is ca. −50 kcal/mol, meaning that the free energy decreases by ~5 kcal/mol upon the formation of 10% native contacts. On the other hand, the landscape of pKID is funneled but considerably shallower (slope of −24 kcal/mol), which explains why pKID is disordered in free environments. Upon binding to KIX, the landscape of pKID now becomes significantly steep (slope of −54 kcal/mol), which enables otherwise disordered pKID to fold. We also show that it is the pKID–KIX intermolecular interactions originating from hydrophobic residues that mainly confer the steep folding funnel. The present work not only provides the quantitative characterization of the protein folding free energy landscape, but also establishes the usefulness of the folding funnel concept to IDPs.

Effects of flexibility and electrostatic interactions on the coupled binding–folding mechanisms of Chz.core and H2A.z–H2B

2017 ◽  
Vol 13 (10) ◽  
pp. 2152-2159 ◽  
Author(s):  
Xu Shang ◽  
Wenting Chu ◽  
Xiakun Chu ◽  
Chuanbo Liu ◽  
Liufang Xu ◽  
...  
Keyword(s):  
Free Energy ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Histone Variant ◽  
Energy Landscapes ◽  
Binding Mechanism ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Binding Preference ◽  
Free Energy Landscapes

The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. The coupled folding–binding mechanism of the complex can be quantified by the free energy landscapes.

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