Binding-and-folding recognition of an intrinsically disordered protein using online learning molecular dynamics
This addresses the atomistic understanding of protein interactions for biological research, but it is incremental as it applies a new method to a specific protein system.
The study tackled the problem of understanding the coupled folding and binding processes of intrinsically disordered proteins by reconstructing the binding and folding between the c-Myb transactivation domain and the KIX domain using a novel unbiased high-throughput adaptive sampling approach, revealing that initial native contacts by leucine residues prime the binding and folding with a mixture of conformational selection and induced fit.
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 $α$-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.