Open AccessFree-energy landscape of molecular interactions between endothelin 1 and human endothelin type B receptor: fly-casting mechanism
Author(s) -
Junichi Higo,
Kota Kasahara,
Masao Wada,
Bhaskar DasGupta,
Narutoshi Kamiya,
Tomonori Hayami,
Ikuo Fukuda,
Yoshifumi Fukunishi,
Haruki Nakamura
Publication year - 2019
Publication title -
protein engineering, design and selection
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.627
H-Index - 109
eISSN - 1741-0134
pISSN - 1741-0126
DOI - 10.1093/protein/gzz029
Subject(s) - energy landscape , chemistry , chemical physics , endothelin receptor , physics , molecular dynamics , receptor , biophysics , stereochemistry , crystallography , biology , computational chemistry , biochemistry
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.