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

Analysis of, θ 2 , d 1 , θ 1 and ϕ 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 twisting, ϕ ( lateral twisting ) 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 d 1 , θ 2 and ϕ 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.