<scp>pH</scp>‐dependent conformational dynamics of beta‐secretase 1: <scp>A</scp> molecular dynamics study

Mermelstein, Daniel J.; McCammon, J. Andrew; Walker, Ross C.

doi:10.1002/jmr.2765

Cited by 20 publications

(17 citation statements)

References 56 publications

(106 reference statements)

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“…S9) shows that all the four ligand poses are different. This analysis suggests that the binding mode of BACE_18 depends on the protonation states of the aspartyl dyad in BACE-1 and is consistent with other studies that evaluate the pH-dependent activity of BACE-1 [46,27,47].…”

Section: Equilibrated Poses From MD Simulations Have Higher Rmsd In Gsupporting

confidence: 90%

D3R Grand Challenge 4: Ligand Similarity and MM-GBSA-Based Pose Prediction and Affinity Ranking for BACE-1 Inhibitors

Sasmal¹,

Khoury²,

Mobley³

2019

Preprint

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The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand Challenge 4, which focused on predicting the binding poses and affinity ranking for compounds targeting the beta-amyloid precursor protein (BACE-1). Our ligand similarity-based protocol using HYBRID (OpenEye Scientific Software) successfully identified poses close to the native binding mode for most of the ligands with less than 2 A RMSD accuracy. Furthermore, we compared the performance of our HYBRID-based approach to that of AutoDock Vina and Dock 6 and found that HYBRID performed better here for pose prediction. We also conducted end-point free energy estimates on protein-ligand complexes using molecular mechanics combined with generalized Born surface area method (MM-GBSA). We found that the binding affinity ranking based on MM-GBSA scores have poor correlation with the experimental values. Finally, the main lessons from our participation in D3R Grand Challenge 4 suggest that: i) the generation of the macrocycles conformers is a key step for successful pose prediction, ii) the protonation states of the BACE-1 binding site should be treated carefully, iii) the MM-GBSA method could not discriminate well between different predicted binding poses, and iv) the MM-GBSA method does not perform well at predicting protein-ligand binding affinities here.

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Section: Equilibrated Poses From MD Simulations Have Higher Rmsd In Gsupporting

confidence: 90%

D3R Grand Challenge 4: Ligand Similarity and MM-GBSA-Based Pose Prediction and Affinity Ranking for BACE-1 Inhibitors

Sasmal¹,

Khoury²,

Mobley³

2019

Preprint

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“…BACE1 is most active in acidic organelles. [169, 170] In sAD, altered endolysosomal trafficking leads to colocalization of AβPP and BACE1 in late endosomes, facilitating Aβ synthesis. [171] Intriguingly, at physiological concentrations, Aβ acts as a potent antioxidant and metal chelator [160–163, 172] that is localized to lipoproteins, and appears to protect vulnerable polyunsaturated cargo from peroxidation.…”

Section: Discussionmentioning

confidence: 99%

Lipid peroxidation induced ApoE receptor-ligand disruption as a unifying hypothesis underlying sporadic Alzheimer’s disease in humans

Ramsden

Keyes

Calzada

et al. 2021

Preprint

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The strong genetic link between Apolipoprotein E (ApoE) and sporadic Alzheimer's disease (AD) and the marked increase in brain lipid peroxidation observed in early AD suggest that dysfunctional lipid metabolism plays a central role in AD pathogenesis. However, specific mechanisms and targets linking ApoE and lipid peroxidation to AD are not well-defined. Here we used a combination of biochemical experiments, single-marker immunohistochemistry (IHC), and multiplex-IHC to examine the hypothesis that synaptic ApoE receptors and their ligands ApoE and Reelin are susceptible to lipid peroxidation, and that downstream disruptions in ApoE delivery and Reelin-ApoE receptor signaling cascades contribute to the pathogenesis of sporadic AD. We found that (1) Lys and His-enriched sequences within the binding regions of ApoER2, ApoE, VLDLR and Reelin, and recombinant ApoER2, ApoE and Reelin proteins, are vulnerable to attack by aldehydic products of lipid peroxidation, generating lipid-protein adducts and acid-stable ApoE receptor-ligand complexes; (2) ApoER2, lipid peroxidation-modified ApoE, native ApoE, Reelin, and multiple downstream components of Reelin-ApoE receptor signaling cascades that govern synaptic integrity [including DAB1, Tyr232-phosphorylated DAB1, Tyr607-phosphorylated Phosphatidylinositol 3-kinase, Thr508-phosphorylated LIM kinase-1, Ser202/Thr205-phosphorylated Tau and Thr19-phosphorylated-PSD95] accumulate in the immediate vicinity of neuritic plaques and surrounding abnormal neurons, and (3) several of these ApoE/Reelin-ApoE receptor-DAB1 pathway markers positively correlate with Braak stage, Aβ plaque load, and antemortem cognitive impairment. ApoE/Reelin-ApoER2-DAB1 axis pathologies were especially prominent in the dendritic compartments of the molecular layer of the dentate gyrus, cornu ammonis and subiculum, regions that receive synaptic input from the entorhinal-hippocampal projections that underlie memory formation. Taken together, these observations point toward extensive derangements in the ApoE/Reelin-ApoE receptor-DAB1 axis and provide evidence supporting a new, working hypothesis wherein lipid peroxidation-induced adduction and crosslinking of ApoE receptors and ApoE are proximate molecular events that compromise synaptic integrity and contribute to the histopathological hallmarks and cognitive deficits that characterize sporadic AD in humans.

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“…Implicit solvent Constant pH MD simulations were performed with the GPU implementation of the PMEMD engine [44] from the Amber software suite [22], along with the Generalized Born solvation model [45,46]. Salt concentration was set to 0.1 M, whereas solvent pH set to 7.0, without any cut-off for the non-bonded interactions.…”

Section: Implicit Solvent Constant Ph Molecular Dynamicsmentioning

confidence: 99%

Revealing the unknown aspects of initial steps of prenylated flavin mononucleotide biosynthesis – the role of Lys129 in PaUbiX

Żaczek

Dybała-Defratyka

2022

Preprint

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Background Prenylated flavin mononucleotide (prFMN) is a recently discovered, heavily modified flavin compound. It is the only known cofactor that enables enzymatic 1,3-dipolar cycloaddition reactions. It is produced by enzymes from the UbiX family, from flavin mononucleotide and either dimethylallyl mono- or diphosphate. prFMN biosynthe-sis is currently reported to be initiated by protonation of the substrate by Glu140. Methods Computational chemistry methods are applied herein - mostly different flavors of molecular dynamics MD, such as Constant pH MD, hybrid Quantum-Mechanical / Molecular Mechanical MD, and classical MD. Results Glu140 competes for a single proton with Lys129 prior to the prFMN biosynthesis but it is the latter that adopted a protonated state throughout most of the simulation time. Lys129 interacts very strongly with Glu140 and it plays a key role in the positioning of the DMAP’s phosphate group within the PaUbiX active site throughout different steps of prFMN biosynthesis Conclusions The role of Lys129 in the functioning of PaUbiX is reported for the first time. The severity of interactions between Glu140, Lys129, and DMAP’s phosphate group might enable an unusual decoupling of phosphate’s protonation from the DMAP’s breakdown. This behavior is most likely conserved throughout the UbiX family to the structur-al resemblance of active sites of those proteins. Significance Mechanistic insights into a crucial biochemical process, biosynthesis of prFMN, are provided. This study, alt-hough purely computational, extends and perfectly complements the knowledge obtained in classical laboratory experiments.

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pH‐dependent conformational dynamics of beta‐secretase 1: A molecular dynamics study

Cited by 20 publications

References 56 publications

D3R Grand Challenge 4: Ligand Similarity and MM-GBSA-Based Pose Prediction and Affinity Ranking for BACE-1 Inhibitors

D3R Grand Challenge 4: Ligand Similarity and MM-GBSA-Based Pose Prediction and Affinity Ranking for BACE-1 Inhibitors

Lipid peroxidation induced ApoE receptor-ligand disruption as a unifying hypothesis underlying sporadic Alzheimer’s disease in humans

Revealing the unknown aspects of initial steps of prenylated flavin mononucleotide biosynthesis – the role of Lys129 in PaUbiX

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