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Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies
Wang, Y.; Yang, F.; Yan, D.; Zeng, Y.; Wei, B.; Chen, J.; He, W. Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies. Molecules2023, 28, 4773.
Wang, Y.; Yang, F.; Yan, D.; Zeng, Y.; Wei, B.; Chen, J.; He, W. Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies. Molecules 2023, 28, 4773.
Wang, Y.; Yang, F.; Yan, D.; Zeng, Y.; Wei, B.; Chen, J.; He, W. Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies. Molecules2023, 28, 4773.
Wang, Y.; Yang, F.; Yan, D.; Zeng, Y.; Wei, B.; Chen, J.; He, W. Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies. Molecules 2023, 28, 4773.
Abstract
The β-amyloid cleaving enzyme 1 (BACE1) is regarded as an important target of drug design toward treatment of Alzheimer's disease (AD). In this study, three separate molecular dynamics (MD) simulations and calculations of binding free energies were carried out to comparatively probe identification mechanism of BACE1 on three inhibitors 60W, 954 and 60X. The analyses on MD trajectories indicate that the presence of three inhibitors influences structural stability, flexibility and internal dynamics of BACE1. Binding free energies calculated by using solvated interaction energy (SIE) and molecular mechanics generalized Born surface area (MM-GBSA) methods reveal that the hydrophobic interactions provide decisive forces for inhibitor-BACE1 binding. The calculations of residue-based free energy decomposition suggest that the sidechains of residues L91, D93, S96, V130, Q134, W137, F169 and I179 play key roles in inhibitor-BACE1 binding, which provides a direction for future drug design toward treatment of AD.
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