ArticleThe journal of physical chemistry letters2018
How Ligand Protonation State Controls Water in Protein-Ligand Binding.
Article in The journal of physical chemistry letters, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 36 citations in OpenAlex.
- Protonation Effects in Protein-Ligand Complexes - A Case Study of Endothiapepsin and Pepstatin A with Computational and Experimental Methods.ChemMedChem · 2025Article
- How to Sample Dozens of Substitutions per Site with λ Dynamics.Journal of chemical theory and computation · 2024Article
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- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Comparative Performance of High-Throughput Methods for Protein pJournal of chemical information and modeling · 2023Article
- GPU-Accelerated All-Atom Particle-Mesh Ewald Continuous Constant pH Molecular Dynamics in Amber.Journal of chemical theory and computation · 2022Article
- Novel US-CpHMD Protocol to Study the Protonation-Dependent Mechanism of the ATP/ADP Carrier.Journal of chemical information and modeling · 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
- Atomistic dynamics of a viral infection process: Release of membrane lytic peptides from a non-enveloped virus.Science advances · 2021Article
- Exploring the pH-Dependent Structure-Dynamics-Function Relationship of Human Renin.Journal of chemical information and modeling · 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
- 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
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The role of water in protein-ligand binding has been an intensely studied topic in recent years; however, how ligand protonation state change perturbs water has not been considered. Here we show that water dynamics and interactions can be controlled by the protonation state of ligand using continuous constant pH molecular dynamics simulations of two closely related model systems, β-secretase 1 and 2 (BACE1 and BACE2), in complex with a small-molecule inhibitor. Simulations revealed that, upon binding, the inhibitor pyrimidine ring remains deprotonated in BACE1 but becomes protonated in BACE2. Pyrimidine protonation results in water displacement, rigidification of the binding pocket, and shift in the ligand binding mode from water-mediated to direct hydrogen bonding. These findings not only support but also rationalize the most recent structure-selectivity data in BACE1 drug design. Binding-induced protonation state changes are likely common; our work offers a glimpse at how modeling protein-ligand binding while allowing ligand titration can further advance the understanding of water and structure-based 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.