LAUSR

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.