Generalized-ensemble method study: A helix-mimetic compound inhibits protein-protein interaction by long-range and short-range intermolecular interactions.
J Comput Chem
; 42(14): 956-969, 2021 05 30.
Article
en En
| MEDLINE
| ID: mdl-33755222
ABSTRACT
A heterocyclic compound mS-11 is a helix-mimetic designed to inhibit binding of an intrinsic disordered protein neural restrictive silence factor/repressor element 1 silencing factor (NRSF/REST) to a receptor protein mSin3B. We apply a generalized ensemble method, multi-dimensional virtual-system coupled molecular dynamics developed by ourselves recently, to a system consisting of mS-11 and mSin3B, and obtain a thermally equilibrated distribution, which is comprised of the bound and unbound states extensively. The lowest free-energy position of mS-11 coincides with the NRSF/REST position in the experimentally-determined NRSF/REST-mSin3B complex. Importantly, the molecular orientation of mS-11 is ordering in a wide region around mSin3B. The resultant binding scenario is When mS-11 is distant from the binding site of mSin3B, mS-11 descends the free-energy slope toward the binding site maintaining the molecular orientation to be advantageous for binding. Then, finally a long and flexible hydrophobic sidechain of mS-11 fits into the binding site, which is the lowest-free-energy complex structure inhibiting NRSF/REST binding to mSin3B.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Represoras
/
Compuestos Heterocíclicos con 2 Anillos
Límite:
Animals
Idioma:
En
Revista:
J Comput Chem
Asunto de la revista:
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón