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. Formation of insoluble amyloid plaques in the vascular and hippocampal areas of the brain characterizes Alzheimer’s disease, a devastating neurodegenerative disorder causing dementia. Site-specific hydrolytic catalysis of β-secretase, or BACE-1, is responsible for production of oligomerative amyloid β-peptide. As the catalytic activity of BACE-1 is pH-dependent and its structural dynamics are intrinsic to the catalysis, we examine the dependence of dynamics of BACE-1 on solution pH and its implications on the catalytic mechanism of BACE-1. Also, we highlight the importance of accurate description of protonation states of the titratable groups in computer-aided drug discovery targeting BACE-1. We hope the understanding of pH dependence of the dynamics and inhibitor binding properties of BACE-1 will aid the structure-based inhibitor design efforts against Alzheimer’s disease.Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria Discovery and a computerized quantitative bio-informatic in silico Development of a Synthetic Gp 46-gp21 derived P400-P197 Peptide mimetic pharmacophore as a potential HTLV-1 Fusion Inhibitor in a mass-action law based new cluster of algorithmsSensing of molecules using quantum dynamics. 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.Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria Discovery and a computerized quantitative bio-informatic in silico Development of a Synthetic Gp 46-gp21 derived P400-P197 Peptide mimetic pharmacophore as a potential HTLV-1 Fusion Inhibitor in a mass-action law based new cluster of algorithmsSensing of molecules using quantum dynamics.
Conformational Dynamics; Binding Free Energies; Inhibitors of BACE-1; Perspective of Protonation; Equilibria Discovery; computerized quantitative bio-informatic; in silico Development; Synthetic Gp 46-gp21; P400-P197 Peptide mimetic; pharmacophore; HTLV-1 Fusion Inhibitor; mass-action law; new cluster of algorithms;Sensing of molecules; quantum dynamics;