Virtual Screening Targeting Dimerization Signals of Two Mycoplasma HU Proteins Revealed Different Types of Inhibitors Interacting with Common Binding Determinants

Abstract

DNA-Binding HU proteins are critical to the maintenance of the nucleoid structure and are promising pharmacological targets for the design of new antibiotics. The virtual screening for low-molecular-weight compounds capable of specifically interacting with the dimerization signals of two mycoplasma HU proteins was performed. The stability of target protein–ligand complexes was evaluated by molecular dynamics simulation. An analysis of the amino-acid environment of the ligands shows that inhibitors targeting the conserved amino-acid sequence, the so-called dimerization signal, which is involved in the formation of HU dimers and the maintenance of their stability and is located in an interdimer beta-sheet, have the second binding site in the alpha-helical domain. The binding determinants of inhibitors at the dimer interfaces of the proteins are identical and are independent of the amino-acid sequence. Consequently, HU proteins have two sites for the formation of the dimer interface, which should be taken into account in the design of inhibitors of dimerization.