Small Molecule Modulation of Intrinsically Disordered Proteins Using Molecular Dynamics Simulations

• DOI: 10.1021/acs.jcim.0c00381
• Publication Date: 2020-08-03T15:49:55Z
• Authors: Pablo Herrera-Nieto; Adrià Pérez; Gianni De Fabritiis
• Keywords: Intrinsically Disordered Proteins; Conformational ensembles

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