Biophysics and Physicobiology
Online ISSN : 2189-4779
ISSN-L : 2189-4779

This article has now been updated. Please use the final version.

Binding free-energy landscapes of small molecule binder and non-binder to FMN riboswitch: All-atom molecular dynamics
Junichi Higo Gert-Jan BekkerNarutoshi KamiyaIkuo FukudaYoshifumi Fukunishi
Author information
JOURNAL OPEN ACCESS Advance online publication
Supplementary material

Article ID: e200047

Details
Abstract

A small and flexible molecule, ribocil A (non-binder) or B (binder), binds to the deep pocket of the aptamer domain of the FMN riboswitch, which is an RNA molecule. This binding was studied by mD-VcMD, which is a generalized-ensemble simulation method. Ribocil A and B are structurally similar because they are optical isomers to each other. In the initial conformation of simulation, the ligands and the aptamer were completely dissociated in explicit solvent. The aptamer–ribocil B binding was stronger than the aptamer–ribocil A binding, which agrees with experiments. The computed free-energy landscape for the aptamer–ribocil B binding was funnel-like, whereas that for the aptamer–ribocil A binding was rugged. When passing through the gate (named “front gate”) of the binding pocket, each ligand interacted with bases of the riboswitch by non-native π-π stackings, and the stackings restrained the ligand’s orientation to be advantageous to reach the binding site smoothly. When the ligands reached the binding site in the pocket, the non-native stackings were replaced by the native stackings. The ligand’s orientation restriction is discussed referring to a selection mechanism reported in an earlier work on a drug–GPCR interaction. The present simulation showed another pathway leading the ligands to the binding site. The gate (“rear gate”) for this pathway was located completely opposite to the front gate on the aptamer’s surface. However, the approach from the rear gate required overcoming a free-energy barrier regarding ligand’s rotation before reaching the binding site.

Fullsize Image
Content from these authors
© 2023 THE BIOPHYSICAL SOCIETY OF JAPAN
feedback
Top