Search

The original etiology of Alzheimer's disease (AD) is the deposition of amyloid-beta (Aβ) proteins, which starts from the aggregation of the Aβ oligomers. The optimal therapeutic strategy targeting Aβ oligomer aggregation is the development of AD vaccines. Despite the fact that positive progress has been made for experimental attempts at AD vaccines, the physicochemical and even structural properties of these AD vaccines remain unclear. In this study, through immunoinformatic and molecular dynamics (MD) simulations, we first designed and simulated an alternative of vaccine TAPAS and found that the structure of the alternative can reproduce the 3D conformation of TAPAS determined experimentally. Meanwhile, immunoinformatic methods were used to analyze the physicochemical properties of TAPAS, including immunogenicity, antigenicity, thermal stability, and solubility, which confirm well the efficacy and safety of the vaccine, and validate the scheme reliability of immunoinformatic and MD simulations in designing and simulating the TAPAS vaccine. Using the same scheme, we predicted the 3D conformation of the optimized ACI-24 peptide vaccine, an Aβ peptide with the first 15 residues of Aβ42 (Aβ1–15). The vaccine was verified once to be effective against both full-length Aβ1–42 and truncated Aβ4–42 aggregates, but an experimental 3D structure was absent. We have also explored the immune mechanism of the vaccine at the molecular level and found that the optimized ACI-24 and its analogues can block the growth of either full-length Aβ1–42 or truncated Aβ4–42 pentamer by contacting the hydrophobic residues within the N-terminus and β1 region on the contact surface of either pentamer. Additionally, residues (D1, D7, S8, H13, and Q15) were identified as the key residues of the vaccine to contact either of the two Aβ oligomers. This work provides a feasible implementation scheme of immunoinformatic and MD simulations for the development of AD small peptide vaccines, validating the power of the scheme as a parallel tool to the experimental approaches and injecting molecular-level information into the understanding and design of anti-AD vaccines. [ABSTRACT FROM AUTHOR]

Context: Existing researches confirmed that β amyloid (Aβ) has a high affinity for the α7 nicotinic acetylcholine receptor (α7nAChR), associating closely to Alzheimer's disease. The majority of related studies focused on the experimental reports on the neuroprotective role of Aβ fragment (Aβx), however, with a lack of investigation into the most suitable binding region and mechanism of action between Aβ fragment and α7nAChR. In the study, we employed four Aβ1–42 fragments Aβx, Aβ1–16, Aβ10–16, Aβ12–28, and Aβ30–42, of which the first three were confirmed to play neuroprotective roles upon directly binding, to interact with α7nAChR. Methods: The protein–ligand docking server of CABS-DOCK was employed to obtain the α7nAChR-Aβx complexes. Only the top α7nAChR-Aβx complexes were used to perform all-atom GROMACS dynamics simulation in combination with Charmm36 force field, by which α7nAChR-Aβx interactions' dynamic behavior and specific locations of these different Aβx fragments were identified. MM-PBSA calculations were also done to estimate the binding free energies and the different contributions from the residues in the Aβx. Two distinct results for the first three and fourth Aβx fragments in binding site, strength, key residue, and orientation, account for why the fourth fails to play a neuroprotective role at the molecular level. [ABSTRACT FROM AUTHOR]

Experimental observations revealed that the amyloid-β 42 oligomer (AβO) can directly bind to the LilrB2 D1D2(LDD) receptor with nanomolar-affinity, leading to changes in synaptic plasticity and cognitive deficits. However, the dependence of neurotoxicity on the morphology, size, and aggregation stage (SP1, SP2) of AβO, as well as the specific molecular mechanism of AβO–LDD interaction, remain uncertain. To address these uncertainties, we investigated the interaction between the LDD neuroreceptor and AβO with different Aβ42 species (nontoxic species, toxic species, and protofibril) and sizes. Our results showed that the LDD selectively binds AβO species rather than the Aβ42 monomer, accommodating various Aβ42 dimers and trimers as well as SP2 AβO, in a specific pose in the pocket of the LDD receptor (region I). Additionally, protofibrils with exposed β1/β2 regions can also bind to region I of the LDD receptor, as observed experimentally (Cao, et al., Nat. Chem., 2018, 10, 1213; and Aim et al., Nat. Commun., 2021, 12, 3451). More extensively, we identified two additional regions of the LDD receptor, regions II and III, suitable for binding to larger AβO species at the SP1 with different molecular weights and conformations, accounting for the stronger binding strength obtained experimentally. We suggest that the two regions are more competitive than region I in causing toxicity by AβO binding. The detailed and systematic characterization for the complexes generated between the LDD receptor and various AβO species, including the protofibril, offers deep insight into the dependence of neurotoxicity on the AβO size and conformation at the molecular level, and provides novel and specific targets for drug design of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The paper reports in silico three modified small molecules, two negatively charged E1C and E2C and one neutral TQ, which show more potent inhibitory effect than their parental molecules CQ3, TS0, and ER on the Cu2+ induced Aβ42 aggregation. In the acidic condition, TQ is the most powerful inhibitor, as it not only decreases the helix content of Cu2+‐Aβ42 complex but also increases the oxidizability; E1C/E2C however decreases the helix content of Cu2+‐Aβ42 complex but also with increased oxidizability, indicating that the inhibitory effect of the two charged molecules depends on the multiple factors, at least including the composite mechanism of helix decrease and oxidizability increase. In the basic condition, any of three modified molecules can increase the helix content of the Cu2+‐Aβ42 complex. Anyway, small molecules containing neutral and larger hydrophobic aromatic groups are always more effective in inhibiting Cu2+‐induced Aβ42 aggregation in both basic and acidic conditions. [ABSTRACT FROM AUTHOR]

Amyloid precursor protein (APP) is the core of the pathogenesis of Alzheimer's disease (AD). Existing studies have shown that the soluble secreted APP (sAPPα) fragment obtained from the hydrolysis of APP by α-secretase has a synaptic function. Thereinto, a nine-residue fragment (APP9mer) of the extension domain region of sAPPα can bind directly and selectively to the N-terminal sushi1 domain (SD1) of the γ-aminobutyric acid type B receptor subunit 1a (GABABR1a) protein, which can influence synaptic transmission and plasticity by changing the GABABR1a conformation. APP9mer is a highly flexible, disordered region, and as such it is difficult to experimentally determine the optimal APPmer-SD1 binding complex. In this study we constructed two types of APP9mer-SD1 complexes through molecular docking and molecular dynamics simulation, aiming to explore the recognition function and mechanism of the specific binding of APP9mer with SD1, from which the most probable APPmer-SD1 model conformation is predicted. All the data from the analyses of RMSD, RMSF, PCA, DCCM and MM/PBSA binding energy as well as comparison with the experimental dissociation constant Kd suggest that 2NC is the most likely conformation to restore the crystal structure of the experimental APP9mer-SD1 complex. Of note, the key recognition residues of APP9mer are D24, D25, D27, W29 and W30, which mainly act on the 9–45 residue domain of SD1 (consisting of two loops and three short β-chains at the N-terminus of SD1). The mini-model with key residues identified establishes the molecular basis with deep insight into the interaction between APP and GABABR1a and provides a target for the development of therapeutic strategies for modulating GABABR1a-specific signaling in neurological and psychiatric disorders. More importantly, the study offers a theoretical solution for how to determine a biomolecular structure with a highly flexible, disordered fragment embedded within. The flexible fragment involved in a protein structure has to be deserted usually during the structural determination with experimental methods (e.g. X-ray crystallography, etc.). [ABSTRACT FROM AUTHOR]