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

2019-08-16 20:35:09 3

Intrinsically Disordered Proteins (IDPs) are proteins that lack a stable three-dimensional native structure under physiological conditions but possess biological functions. They are involved in various critical physiological processes such as transcription and translation regulation, cellular signal transduction, and protein phosphorylation. IDPs are a challenge or amendment to the conventional sequence-structure-function paradigm for proteins. At the same time, they are widely associated with human diseases and may serve as potential drug design targets.

The group of Assoc. Prof. Zhirong Liu in Center for Quantitative Biology (CQB), Peking University, used molecular modeling to investigated the properties of IDPs, and have obtained some results in the past years: to reveal the origin of the kinetic advantages of IDPs [J. Mol. Biol. 393, 1143 (2009), which was higligted by Faculty of 1000 Biology]; to propose the concept of “buffer effect” for molecular recognition of IDPs [Proteins 78, 3251 (2010); PLoS ONE 5, 15375 (2010)]; reveal the special enthalpy-entropy compensation in protein-protein binding of IDPs and its effect on the specificity [Int. J. Mol. Sci. 12, 1410 (2011); Chem. Eur. J. 19, 4462 (2013)]; and to reveal the inherent relationships among different biophysical prediction methods for IDPs [Biophys. J.104, 488 (2013)]. Recently, they collaborated with Prof. Luhua Lai in CQB to reveal the “cloud” interaction between IDPs and ligands.

IDPs are important drug design targets. However, drug design targeting IDPs is still in the very early stages, and 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, the groups of Prof. Liu and Prof. Lai performed extensive simulations on the oncoprotein c-Myc and its binding to a reported small molecule inhibitor, ligand 10074-A4. 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. The proposed concept of “ligand cloud” highlight the special specificity of IDPs in molecular recognition.

Figure: The ligand (purple dots) binds to intrinsically disordered protein (c-Myc) at different sites along the chain and behaves like "ligand clouds" (purple clouds).

This study was published as a cover paper and Featured Research in PLoS Computational Biology 9 (10): e1003249/1-11 (2013) with authors of Fan Jin, Chen Yu, Luhuai Lai*, and Zhirong Liu*. It was highlighted by the editor as “providing insights that may help improve rational drug design”. The first author (Fan Jin) is a graduate student in CQB directed by Prof. Liu, and the second author (Chen Yu) is a graduate student in College of Chemistry and Molecular Engineering directed by Prof. Lai.

This work was supported by the Ministry of Science and Technology and the National Natural Science Foundation of China.