Small Molecule Modulation of Intrinsically Disordered Proteins Using Molecular Dynamics Simulations

J Chem Inf Model. 2020 Oct 26;60(10):5003-5010. doi: 10.1021/acs.jcim.0c00381. Epub 2020 Aug 15.

Abstract

The extreme dynamic behavior of intrinsically disordered proteins hinders the development of drug-like compounds capable of modulating them. There are several examples of small molecules that specifically interact with disordered peptides. However, their mechanisms of action are still not well understood. Here, we use extensive molecular dynamics simulations combined with adaptive sampling algorithms to perform free ligand binding studies in the context of intrinsically disordered proteins. We tested this approach in the system composed by the D2 sub-domain of the disordered protein p27 and the small molecule SJ403. The results show several protein-ligand bound states characterized by the establishment of a loosely oriented interaction mediated by a limited number of contacts between the ligand and critical residues of p27. Finally, protein conformations in the bound state are likely to be explored by the isolated protein too, therefore supporting a model where the addition of the small molecule restricts the available conformational space.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Intrinsically Disordered Proteins*
  • Ligands
  • Molecular Dynamics Simulation
  • Peptides
  • Protein Conformation

Substances

  • Intrinsically Disordered Proteins
  • Ligands
  • Peptides