Binding mechanism of spinosine and venenatine molecules with p300 HAT enzyme: Molecular screening, molecular dynamics and free-energy analysis

Abstract

The chromatin modification is regulated by the histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) enzymes; abnormal function of these enzymes leads to several malignant diseases. The inhibition of these enzymes using natural ligand molecules is an emerging technique to cure these diseases. The in vitro analysis of natural molecules, venenatine, spinosine, palmatine and taxodione are giving the best inhibition rate against p300 HAT enzyme. However, the detailed understanding of binding and the stability of these molecules with p300 HAT is not yet known. The aim of the present study is focused to determine the binding strength of the molecules from molecular dynamics simulation analysis. The docking analysis confirms that, the venenatine (-6.97 kcal/mol - conformer 8), spinosine (-6.52 kcal/mol conformer -10), palmatine (-5.72 kcal/mol conformer-3) and taxodione (-4.99 kcal/mol conformer-4) molecules form strong hydrogen bonding interactions with the key amino acid residues (Arg1410, Thr1411 and Trp1466) present in the active site of p300. In the molecular dynamics (MD) simulation, the spinosine retain these key interactions with the active site amino acid residues (Arg1410, Thr1411, and Trp1466) than venenatine and are stable throughout the simulation. The RMSD value of spinosine (0.5 to 1.3 Å) and venenatine (0.3 to 1.3 Å) are almost equal during the MD simulation. However, during the MD simulation, the intermolecular interaction between venenatine and the active site amino acid residues (Arg1410, Thr1411, and Trp1466) decreased on comparing with the spinosine-p300 interaction. The binding free energy of the spinosine (-15.30 kcal/mol) is relatively higher than the venenatine (-11.8 kcal/mol); this increment is attributed to the strong hydrogen bonding interactions of spinosine molecule with the active site amino acid residues of p300.

Keywords: free energy calculations; molecular docking; molecular dynamics simulation; normal mode analysis; principal component analysis.