Ligand Clouds around Protein Clouds: A Scenario of Ligand Binding with Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) were found to be widely associated with human diseases and may serve as potential drug design targets. However, drug design targeting IDPs is still in the very early stages. Progress in drug design is usually achieved using experimental screening; however, the structural disorder of IDPs makes it difficult to characterize their interaction with ligands using experiments alone. To better understand the structure of IDPs and their interactions with small molecule ligands, we performed extensive simulations on the c-Myc370–409 peptide and its binding to a reported small molecule inhibitor, ligand 10074-A4. We found that the conformational space of the apo c-Myc370–409 peptide was rather dispersed and that the conformations of the peptide were stabilized mainly by charge interactions and hydrogen bonds. Under the binding of the ligand, c-Myc370–409 remained disordered. The ligand was found to bind to c-Myc370–409 at different sites along the chain and behaved like a ‘ligand cloud’. In contrast to ligand binding to more rigid target proteins that usually results in a dominant bound structure, ligand binding to IDPs may better be described as ligand clouds around protein clouds. Nevertheless, the binding of the ligand and a non-ligand to the c-Myc370–409 target could be clearly distinguished. The present study provides insights that will help improve rational drug design that targets IDPs.Author Summary: Intrinsically disordered proteins (IDPs) exist as conformational ensembles that change rapidly. They are an important and common class of proteins in all kingdoms of life. IDPs are widely associated with human diseases and may serve as potential drug design targets. However, drug design targeting IDPs is difficult and only limited examples have been reported. One example is the oncoprotein, c-Myc, for which seven inhibitors were discovered by experimental screening. Understanding how small inhibitor molecules bind to c-Myc may help in understanding the binding mechanism of IDPs with ligands. In the present study, we conducted extensive molecular dynamics simulations to explore the binding mechanism for the c-Myc peptide with an inhibitor 10074-A4. We found that 10074-A4 could bind to c-Myc370–409 at different sites along the peptide chain and its binding behavior could be described as a ‘ligand cloud’. Even in the bound state, the structure of the c-Myc370–409 peptide remained a dynamic ensemble. Compared to c-Myc peptides that do not bind to 10074-A4, c-Myc370–409 binds selectively with 10074-A4, but the specificity of binding was not high. The interactions of IDPs with ligands can perhaps be described as a scenario in which ligand clouds around protein clouds.