ArticlePLoS computational biology2015
Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria.
Article in PLoS computational biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 40 citations in OpenAlex.
- Computing the pH-Dependent Thermodynamics of the Allostery between Dimerization and Palmitate Binding in β-Lactoglobulin.The journal of physical chemistry. B · 2025Article
- Accurately Predicting Protein pJournal of chemical theory and computation · 2023Article
- Scalable Constant pH Molecular Dynamics in GROMACS.Journal of chemical theory and computation · 2022Article
- Approach to Study pH-Dependent Protein Association Using Constant-pH Molecular Dynamics: Application to the Dimerization of β-Lactoglobulin.Journal of chemical theory and computation · 2022Article
- Titr-DMD-A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework.Journal of chemical theory and computation · 2021Article
- Estimating the Roles of Protonation and Electronic Polarization in Absolute Binding Affinity Simulations.Journal of chemical theory and computation · 2021Article
- D3R Grand Challenge 4: ligand similarity and MM-GBSA-based pose prediction and affinity ranking for BACE-1 inhibitors.Journal of computer-aided molecular design · 2020Article
- Best Practices for Alchemical Free Energy Calculations [Article v1.0].Living journal of computational molecular science · 2020Article
- Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4.Journal of computer-aided molecular design · 2019Article
- pH-dependent conformational dynamics of beta-secretase 1: A molecular dynamics study.Journal of molecular recognition : JMR · 2019Article
- How Ligand Protonation State Controls Water in Protein-Ligand Binding.The journal of physical chemistry letters · 2018Article
- Combining in vitro and in silico Approaches to Find New Candidate Drugs Targeting the Pathological Proteins Related to the Alzheimer's Disease.Current neuropharmacology · 2018Review
- Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for β-Secretase.The journal of physical chemistry letters · 2017Article
- Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease.Journal of molecular modeling · 2017Article
- Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors.The journal of physical chemistry letters · 2016Article
- Computation of pH-dependent binding free energies.Biopolymers · 2016Review
- The molecular basis for the pH-dependent calcium affinity of the pattern recognition receptor langerin.The Journal of biological chemistryArticle
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3 authors at 2 institutions in 1 country.
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Abstract
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.
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