ArticleThe journal of physical chemistry letters2017
Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for β-Secretase.
Article in The journal of physical chemistry letters, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 36 citations in OpenAlex.
- Constant-pH Molecular Dynamics of Cationic Peptide Dendrimers Binding to siRNA.Journal of chemical information and modeling · 2026Article
- Computing the pH-Dependent Thermodynamics of the Allostery between Dimerization and Palmitate Binding in β-Lactoglobulin.The journal of physical chemistry. B · 2025Article
- The role of ribosomal protein networks in ribosome dynamics.Nucleic acids research · 2025Article
- Fluorine Atoms on CInternational journal of molecular sciences · 2022Article
- Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer's Disease Therapy.Molecules (Basel, Switzerland) · 2022Article
- A fine balance of hydrophobic-electrostatic communication pathways in a pH-switching protein.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Exploring the pH- and Ligand-Dependent Flap Dynamics of Malarial Plasmepsin II.Journal of chemical information and modeling · 2022Article
- A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0].Living journal of computational molecular science · 2022Article
- Unravelling Constant pH Molecular Dynamics in Oligopeptides with Explicit Solvation Model.Polymers · 2021Article
- Continuous Constant pH Molecular Dynamics Simulations of Transmembrane Proteins.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Assessment of proton-coupled conformational dynamics of SARS and MERS coronavirus papain-like proteases: Implication for designing broad-spectrum antiviral inhibitors.The Journal of chemical physics · 2020Article
- Exploring pH Dependent Host/Guest Binding Affinities.The journal of physical chemistry. B · 2020Article
- Scalable molecular dynamics on CPU and GPU architectures with NAMD.The Journal of chemical physics · 2020Article
- Allosteric discrimination at the NADH/ADP regulatory site of glutamate dehydrogenase.Protein science : a publication of the Protein Society · 2019Article
- GPU-Accelerated Implementation of Continuous Constant pH Molecular Dynamics in Amber: pJournal of chemical information and modeling · 2019Article
- How Electrostatic Coupling Enables Conformational Plasticity in a Tyrosine Kinase.Journal of the American Chemical Society · 2019Article
- Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules.Journal of the American Chemical Society · 2019Article
- How Ligand Protonation State Controls Water in Protein-Ligand Binding.The journal of physical chemistry letters · 2018Article
- Assessment of a Single Decoupling Alchemical Approach for the Calculation of the Absolute Binding Free Energies of Protein-Peptide Complexes.Frontiers in molecular biosciences · 2018Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Many important pharmaceutical targets, such as aspartyl proteases and kinases, exhibit pH-dependent dynamics, functions and inhibition. Accurate prediction of their binding free energies is challenging because current computational techniques neglect the effects of pH. Here we combine free energy perturbation calculations with continuous constant pH molecular dynamics to explore the selectivity of a small-molecule inhibitor for β-secretase (BACE1), an important drug target for Alzheimer's disease. The calculations predicted identical affinity for BACE1 and the closely related cathepsin D at high pH; however, at pH 4.6 the inhibitor is selective for BACE1 by 1.3 kcal/mol, in excellent agreement with experiment. Surprisingly, the pH-dependent selectivity can be attributed to the protonation of His45, which allosterically modulates a loop-inhibitor interaction. Allosteric regulation induced by proton binding is likely common in biology; considering such allosteric sites could lead to exciting new opportunities in drug design.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.