ArticleJournal of chemical theory and computation2006
Assigning the protonation states of the key aspartates in β-Secretase using QM/MM X-ray structure refinement.
Article in Journal of chemical theory and computation, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 83 citations in OpenAlex.
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.Communications biology · 2023Article
- Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer's Disease.International journal of molecular sciences · 2019Review
- Predicting protein-ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A.Chemical science · 2019Article
- Solving the scalability issue in quantum-based refinement: Q|R#1.Acta crystallographica. Section D, Structural biology · 2017Article
- Quantum crystallography.Chemical science · 2017Review
- Q|R: quantum-based refinement.Acta crystallographica. Section D, Structural biology · 2017Article
- XModeScore: a novel method for accurate protonation/tautomer-state determination using quantum-mechanically driven macromolecular X-ray crystallographic refinement.Acta crystallographica. Section D, Structural biology · 2016Article
- Determination of the protonation state of the Asp dyad: conventional molecular dynamics versus thermodynamic integration.Journal of molecular modeling · 2016Article
- Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria.PLoS computational biology · 2015Article
- Polyphenols as therapeutic molecules in Alzheimer's disease through modulating amyloid pathways.Molecular neurobiology · 2015Review
- Using quantum mechanical approaches to study biological systems.Accounts of chemical research · 2014Article
- Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β -Secretase.Scientifica · 2014Review
- Conformational analysis and parallel QM/MM X-ray refinement of protein bound anti-Alzheimer drug donepezil.Journal of chemical theory and computation · 2013Article
- Conformational Analysis of Free and Bound Retinoic Acid.Journal of chemical theory and computation · 2012Article
- Quantum mechanics study of the hydroxyethylamines-BACE-1 active site interaction energies.Journal of computer-aided molecular design · 2011Article
- Computational alanine scanning with linear scaling semiempirical quantum mechanical methods.Proteins · 2010Article
- QM/MM X-ray refinement of zinc metalloenzymes.Journal of inorganic biochemistry · 2010Article
- Conformational variability of benzamidinium-based inhibitors.Journal of the American Chemical Society · 2009Article
- Critical assessment of quantum mechanics based energy restraints in protein crystal structure refinement.Protein science : a publication of the Protein Society · 2006Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
β-Secretase, a.k.a. β-APP cleaving enzyme (BACE), is an aspartyl protease that has been implicated as a key target in the pathogenesis of Alzheimer's disease (AD). The identification of the protonation states of the key aspartates in β-secretase is of great interest both in understanding the reaction mechanism and in guiding the design of drugs against AD. However, the resolutions of currently available crystal structures for BACE are not sufficient to determine the hydrogen atom locations. We have assigned the protonation states of the key aspartates using a novel method, QM/MM X-ray refinement. In our approach, an energy function is introduced to the refinement where the atoms in the active site are modeled by quantum mechanics (QM) and the other atoms are represented by molecular mechanics (MM). The gradients derived from the QM/MM energy function are combined with those from the X-ray target to refine the crystal structure of a complex containing BACE and an inhibitor. A total number of 8 protonation configurations of the aspartyl dyad were considered and QM/MM X-ray refinements were performed for all of them. The relative stability of the refined structures was scored by constructing the thermodynamic cycle using the energetics calculated by fully quantum mechanical self-consistent reaction field (QM/SCRF) calculations. While all 8 refined structures fit the observed electron density about equally well, we find the mono-protonated configurations to be strongly favored energetically, especially the configuration with the inner oxygen of Asp32 protonated and the hydroxyl of the inhibitor pointing towards Asp228. It was also found that these results depend on the constraints imposed by the X-ray data. We suggest that one of the strengths of this approach is that the resulting structures are a consensus of theoretical and experimental data and remark on the significance of our results in structure based drug design and mechanistic studies.
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