Molecular mechanism underlying effect of D93 and D289 protonation states on inhibitor-BACE1 binding: exploration from multiple independent Gaussian accelerated molecular dynamics and deep learning

• DOI: 10.1080/1062936x.2024.2419911
• Publication Date: 2024-11-08T08:49:59Z
• Authors: J. Du; G. Xu; W. Zhang; J. Cong; X. Si; B. Wei
• Keywords: Molecular mechanics

BACE1 has been regarded as an essential drug design target for treating Alzheimer's disease (AD). Multiple independent Gaussian accelerated molecular dynamics simulations (GaMD), deep learning (DL), and mechanics general Born surface area (MM-GBSA) method are integrated to elucidate the mechanism underlying effect of D93 D289 protonation on binding inhibitors OV6 4B2 BACE1. The GaMD trajectory-based DL successfully identifies significant function domains. Dynamic analysis shows that strongly affects structural flexibility dynamic behaviour Free energy landscapes indicate inhibitor-bound BACE1s have more conformational states in protonated than wild-type (WT) BACE1, show poses inhibitors. Binding affinities calculated using MM-GBSA highly disturbs ability In addition, two residues significantly hydrogen bonding interactions (HBIs) with altering their activity hot spots recognized by residue-based free estimations provide rational targeting sites towards This study is anticipated theoretical aids development treatment AD.