Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria

BACE-1 is the β-secretase responsible for the initial amyloidogenesis in Alzheimer's disease, catalyzing hydrolytic cleavage of substrate in a pH-sensitive manner. The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspartyl dyad to the substrate, as well as structura...

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Bibliographic Details
Published in:PLoS computational biology 2015-10, Vol.11 (10), p.e1004341-e1004341
Main Authors: Kim, M Olivia, Blachly, Patrick G, McCammon, J Andrew
Format: Article
Language:English
Subjects:
Alzheimer's disease
Alzheimers disease
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - ultrastructure
Amyloidosis
Analysis
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - ultrastructure
Binding Sites
Catalysis
Chemical properties
Energy Transfer
Enzyme Inhibitors - chemistry
Enzymes
Equilibrium
Flexibility
Ligands
Models, Chemical
Molecular Dynamics Simulation
Protein Binding
Protein Conformation
Proteins
Protons
Structure-Activity Relationship
Thermodynamics
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Summary:BACE-1 is the β-secretase responsible for the initial amyloidogenesis in Alzheimer's disease, catalyzing hydrolytic cleavage of substrate in a pH-sensitive manner. The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspartyl dyad to the substrate, as well as structural flexibility in the flap region. Thus, the coupling of protonation and conformational equilibria is essential to a full in silico characterization of BACE-1. In this work, we perform constant pH replica exchange molecular dynamics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine the effect of pH on dynamics and inhibitor binding properties of BACE-1. In our simulations, we find that solution pH controls the conformational flexibility of apo BACE-1, whereas bound inhibitors largely limit the motions of the holo enzyme at all levels of pH. The microscopic pKa values of titratable residues in BACE-1 including its aspartyl dyad are computed and compared between apo and inhibitor-bound states. Changes in protonation between the apo and holo forms suggest a thermodynamic linkage between binding of inhibitors and protons localized at the dyad. Utilizing our recently developed computational protocol applying the binding polynomial formalism to the constant pH molecular dynamics (CpHMD) framework, we are able to obtain the pH-dependent binding free energy profiles for various BACE-1-inhibitor complexes. Our results highlight the importance of correctly addressing the binding-induced protonation changes in protein-ligand systems where binding accompanies a net proton transfer. This work comprises the first application of our CpHMD-based free energy computational method to protein-ligand complexes and illustrates the value of CpHMD as an all-purpose tool for obtaining pH-dependent dynamics and binding free energies of biological systems.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1004341