Investigation of flap flexibility of β-secretase using molecular dynamic simulations

Abstract

<p>Flap motif and its dynamics were extensively reported in aspartate proteases, e.g. HIV proteases and plasmepsins. Herein, we report the first account of flap dynamics amongst different conformations of β-secretase using molecular dynamics simulation. Various parameters were proposed and a selected few were picked which could appropriately describe the flap motion. Three systems were studied, namely Free (BACE_Free) and two ligand-bound conformations, which belonged to space groups P6₁22 (BACE_Bound1) and C222₁ (BACE_Bound2), respectively and four parameters (distance between the flaps tip residue, Thr72 and Ser325, <i>d</i>₁; dihedral angle, <i>ϕ</i> (Thr72-Asp32-Asp228-Ser325); TriCα angles, <i>θ</i>₁ (Thr72-Asp32-Ser325), and <i>θ</i>₂ (Thr72-Asp228-Ser325)) were proposed to understand the change in dynamics of flap domain and the extent of flap opening and closing. Analysis of, <i>θ</i>₂, <i>d</i>₁, <i>θ</i>₁ and <i>ϕ</i> confirmed that the BACE_Free adopted semi-open, open and closed conformations with slight twisting during flap opening. However, BACE_Bound1 (P6122) showed an adaptation to open conformation due to lack of hydrogen bond interaction between the ligand and flap tip residue. A slight flap <i>twisting, ϕ</i> (<i>lateral twisting</i>) was observed for BACE_Bound1 during flap opening which correlates with the opening of BACE_Free. Contradictory to the BACE_Bound1, the BACE_Bound2 locked the flap in a closed conformation throughout the simulation due to formation of a stable hydrogen bond interaction between the flap tip residue and ligand. Analyses of all three systems highlight that <i>d</i>₁, <i>θ</i>₂ and <i>ϕ</i> can be precisely used to describe the extent of flap opening and closing concurrently with snapshots along the molecular dynamics trajectory across several conformations of β-secretase.</p