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

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

© 2021 Wiley Periodicals LLC.

Bibliographische Detailangaben
Veröffentlicht in:Journal of computational chemistry. - 1984. - 42(2021), 14 vom: 30. Mai, Seite 956-969
1. Verfasser: Higo, Junichi (VerfasserIn)
Weitere Verfasser: Takashima, Hajime, Fukunishi, Yoshifumi, Yoshimori, Atsushi
Format: Online-Aufsatz
Sprache:English
Veröffentlicht: 2021
Zugriff auf das übergeordnete Werk:Journal of computational chemistry
Schlagworte:Journal Article Research Support, Non-U.S. Gov't enhanced sampling free-energy landscape generalized ensemble inhibition molecular binding Heterocyclic Compounds, 2-Ring MS-11 compound Repressor Proteins Sin3b protein, mouse
Beschreibung
Zusammenfassung:© 2021 Wiley Periodicals LLC.
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
Beschreibung:Date Completed 18.10.2021
Date Revised 18.10.2021
published: Print-Electronic
Citation Status MEDLINE
ISSN:1096-987X
DOI:10.1002/jcc.26516