Binding-and-folding recognition of an intrinsically disordered protein using online learning molecular dynamics

TL;DR

This study employs an innovative adaptive sampling method to elucidate the atomistic details of how an intrinsically disordered protein folds and binds, revealing the sequence of events and key residues involved.

Contribution

It introduces a novel unbiased high-throughput adaptive sampling approach to study coupled folding and binding in disordered proteins at atomistic resolution.

Findings

Leu298 to Leu302 residues initiate binding and folding.

Binding involves a mixture of conformational selection and induced fit.

Folding occurs upon or during binding, not prior to it.

Abstract

Intrinsically disordered proteins participate in many biological processes by folding upon binding with other proteins. However, coupled folding and binding processes are not well understood from an atomistic point of view. One of the main questions is whether folding occurs prior to or after binding. Here we use a novel unbiased high-throughput adaptive sampling approach to reconstruct the binding and folding between the disordered transactivation domain of \mbox{c-Myb} and the KIX domain of the CREB-binding protein. The reconstructed long-term dynamical process highlights the binding of a short stretch of amino acids on \mbox{c-Myb} as a folded $\alpha$-helix. Leucine residues, specially Leu298 to Leu302, establish initial native contacts that prime the binding and folding of the rest of the peptide, with a mixture of conformational selection on the N-terminal region with an induced fit of the C-terminal.