A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations
Amyloid-β (Aβ<sub>1–42</sub>) peptides aggregated into plaques deposited in the brain are the main hallmark of Alzheimer’s disease (AD), a social and economic burden worldwide. In this context, insoluble Aβ<sub>1–42</sub> fibrils are the main components of plaques. The recent...
محفوظ في:
| المؤلف الرئيسي: | |
|---|---|
| مؤلفون آخرون: | |
| منشور في: |
2024
|
| الموضوعات: | |
| الوسوم: |
إضافة وسم
لا توجد وسوم, كن أول من يضع وسما على هذه التسجيلة!
|
| _version_ | 1852026563638329344 |
|---|---|
| author | Subramanian Boopathi (8733639) |
| author2 | Ramón Garduño-Juárez (10702425) |
| author2_role | author |
| author_facet | Subramanian Boopathi (8733639) Ramón Garduño-Juárez (10702425) |
| author_role | author |
| dc.creator.none.fl_str_mv | Subramanian Boopathi (8733639) Ramón Garduño-Juárez (10702425) |
| dc.date.none.fl_str_mv | 2024-09-18T16:38:17Z |
| dc.identifier.none.fl_str_mv | 10.1021/acschemneuro.4c00383.s002 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/A_Small_Molecule_Impedes_the_A_sub_1_42_sub_Tetramer_Neurotoxicity_by_Preserving_Membrane_Integrity_Microsecond_Multiscale_Simulations/27055451 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Medicine Cell Biology Neuroscience Pharmacology Immunology Computational Biology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Physical Sciences not elsewhere classified unrestricted conformational flexibility reduced conformational changes positively charged residues explicit solvent model economic burden worldwide bottom bilayer leaflet bilayer surface due bilayer hydrophobic region small molecule impedes mounting evidence envisages m30 molecules bind affected mice memory aa )/ coarse membrane phosphate groups membrane bilayer organization deep tetramer penetration conformational stable aβ preserving membrane integrity oligomers ’ interactions cg md simulations membrane bilayer termed m30 severely affected experimental evidence aβ molecule oligomer ’ alzheimer ’ dmpc bilayer μs aa vivo </ vitro </ tetramer structure tetramer penetrates tetramer neurotoxicity tetramer dissociation soluble aβ significantly perturb rigid structure recent trials observations support membrane contacts md simulations main hallmark main components insoluble aβ improving ad hydrogen bonds findings suggest fibril interactions enhanced rigidity embedded aβ demanding tasks close contact associated complex ad ), |
| dc.title.none.fl_str_mv | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | Amyloid-β (Aβ<sub>1–42</sub>) peptides aggregated into plaques deposited in the brain are the main hallmark of Alzheimer’s disease (AD), a social and economic burden worldwide. In this context, insoluble Aβ<sub>1–42</sub> fibrils are the main components of plaques. The recent trials that used approved AD drugs show that they can remove the fibrils from AD patients’ brains, but they did not halt the course of the disease. Mounting evidence envisages that the soluble Aβ<sub>1–42</sub> oligomers’ interactions with the neuronal membrane trigger higher cell death than Aβ<sub>1–42</sub> fibril interactions. Developing a compound that can alleviate the oligomer’s toxicity is one of the most demanding tasks for curing the disease. We performed two molecular dynamics (MD) simulations in an explicit solvent model. In the first case, 55-μs of multiscale all-atom (AA)/coarse-grained (CG) MD simulations were carried out to decipher the impact of a previously described small anti-Aβ molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), on an Aβ<sub>1–42</sub> tetramer structure in close contact with a DMPC bilayer. In the second case, 15-μs AA/CG MD simulations were performed to rationalize the dynamics between Aβ<sub>1–42</sub> and Aβ<sub>1–42</sub>-M30 tetramer complexes embedded in DMPC. On the membrane bilayer, we found that the Aβ<sub>1–42</sub> tetramer penetrates the bilayer surface due to unrestricted conformational flexibility and many contacts with the membrane phosphate groups. In contrast, no Aβ<sub>1–42</sub>-M30 tetramer penetration was observed during the entire course of the simulation. In the case of the membrane-embedded Aβ<sub>1–42</sub> tetramer, the integrity of the bottom bilayer leaflet was severely affected by the interactions between the negatively charged phosphate groups and the positively charged residues of the Aβ<sub>1–42</sub> tetramer, resulting in a deep tetramer penetration into the bilayer hydrophobic region. These contacts were not observed in the case of the membrane-embedded Aβ<sub>1–42</sub>-M30 tetramer. It was noted that M30 molecules bind to Aβ<sub>1–42</sub> tetramer through hydrogen bonds, resulting in a conformational stable Aβ<sub>1–42</sub>-M30 complex. The associated complex has reduced conformational changes and an enhanced rigidity that prevents the tetramer dissociation by interfering with the tetramer-membrane contacts. Our findings suggest that the M30 molecules could bind to Aβ<sub>1–42</sub> tetramer resulting in a rigid structure, and that such complexes do not significantly perturb the membrane bilayer organization. These observations support the <i>in vitro</i> and <i>in vivo</i> experimental evidence that the M30 molecules prevent synaptotocity, improving AD-affected mice memory. |
| eu_rights_str_mv | openAccess |
| id | Manara_84db973abd1edbb0aee9cf2df9b1aa52 |
| identifier_str_mv | 10.1021/acschemneuro.4c00383.s002 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/27055451 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale SimulationsSubramanian Boopathi (8733639)Ramón Garduño-Juárez (10702425)BiophysicsBiochemistryMedicineCell BiologyNeurosciencePharmacologyImmunologyComputational BiologyBiological Sciences not elsewhere classifiedChemical Sciences not elsewhere classifiedPhysical Sciences not elsewhere classifiedunrestricted conformational flexibilityreduced conformational changespositively charged residuesexplicit solvent modeleconomic burden worldwidebottom bilayer leafletbilayer surface duebilayer hydrophobic regionsmall molecule impedesmounting evidence envisagesm30 molecules bindaffected mice memoryaa )/ coarsemembrane phosphate groupsmembrane bilayer organizationdeep tetramer penetrationconformational stable aβpreserving membrane integrityoligomers ’ interactionscg md simulationsmembrane bilayertermed m30severely affectedexperimental evidenceaβ moleculeoligomer ’alzheimer ’dmpc bilayerμs aavivo </vitro </tetramer structuretetramer penetratestetramer neurotoxicitytetramer dissociationsoluble aβsignificantly perturbrigid structurerecent trialsobservations supportmembrane contactsmd simulationsmain hallmarkmain componentsinsoluble aβimproving adhydrogen bondsfindings suggestfibril interactionsenhanced rigidityembedded aβdemanding tasksclose contactassociated complexad ),Amyloid-β (Aβ<sub>1–42</sub>) peptides aggregated into plaques deposited in the brain are the main hallmark of Alzheimer’s disease (AD), a social and economic burden worldwide. In this context, insoluble Aβ<sub>1–42</sub> fibrils are the main components of plaques. The recent trials that used approved AD drugs show that they can remove the fibrils from AD patients’ brains, but they did not halt the course of the disease. Mounting evidence envisages that the soluble Aβ<sub>1–42</sub> oligomers’ interactions with the neuronal membrane trigger higher cell death than Aβ<sub>1–42</sub> fibril interactions. Developing a compound that can alleviate the oligomer’s toxicity is one of the most demanding tasks for curing the disease. We performed two molecular dynamics (MD) simulations in an explicit solvent model. In the first case, 55-μs of multiscale all-atom (AA)/coarse-grained (CG) MD simulations were carried out to decipher the impact of a previously described small anti-Aβ molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), on an Aβ<sub>1–42</sub> tetramer structure in close contact with a DMPC bilayer. In the second case, 15-μs AA/CG MD simulations were performed to rationalize the dynamics between Aβ<sub>1–42</sub> and Aβ<sub>1–42</sub>-M30 tetramer complexes embedded in DMPC. On the membrane bilayer, we found that the Aβ<sub>1–42</sub> tetramer penetrates the bilayer surface due to unrestricted conformational flexibility and many contacts with the membrane phosphate groups. In contrast, no Aβ<sub>1–42</sub>-M30 tetramer penetration was observed during the entire course of the simulation. In the case of the membrane-embedded Aβ<sub>1–42</sub> tetramer, the integrity of the bottom bilayer leaflet was severely affected by the interactions between the negatively charged phosphate groups and the positively charged residues of the Aβ<sub>1–42</sub> tetramer, resulting in a deep tetramer penetration into the bilayer hydrophobic region. These contacts were not observed in the case of the membrane-embedded Aβ<sub>1–42</sub>-M30 tetramer. It was noted that M30 molecules bind to Aβ<sub>1–42</sub> tetramer through hydrogen bonds, resulting in a conformational stable Aβ<sub>1–42</sub>-M30 complex. The associated complex has reduced conformational changes and an enhanced rigidity that prevents the tetramer dissociation by interfering with the tetramer-membrane contacts. Our findings suggest that the M30 molecules could bind to Aβ<sub>1–42</sub> tetramer resulting in a rigid structure, and that such complexes do not significantly perturb the membrane bilayer organization. These observations support the <i>in vitro</i> and <i>in vivo</i> experimental evidence that the M30 molecules prevent synaptotocity, improving AD-affected mice memory.2024-09-18T16:38:17ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acschemneuro.4c00383.s002https://figshare.com/articles/dataset/A_Small_Molecule_Impedes_the_A_sub_1_42_sub_Tetramer_Neurotoxicity_by_Preserving_Membrane_Integrity_Microsecond_Multiscale_Simulations/27055451CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/270554512024-09-18T16:38:17Z |
| spellingShingle | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations Subramanian Boopathi (8733639) Biophysics Biochemistry Medicine Cell Biology Neuroscience Pharmacology Immunology Computational Biology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Physical Sciences not elsewhere classified unrestricted conformational flexibility reduced conformational changes positively charged residues explicit solvent model economic burden worldwide bottom bilayer leaflet bilayer surface due bilayer hydrophobic region small molecule impedes mounting evidence envisages m30 molecules bind affected mice memory aa )/ coarse membrane phosphate groups membrane bilayer organization deep tetramer penetration conformational stable aβ preserving membrane integrity oligomers ’ interactions cg md simulations membrane bilayer termed m30 severely affected experimental evidence aβ molecule oligomer ’ alzheimer ’ dmpc bilayer μs aa vivo </ vitro </ tetramer structure tetramer penetrates tetramer neurotoxicity tetramer dissociation soluble aβ significantly perturb rigid structure recent trials observations support membrane contacts md simulations main hallmark main components insoluble aβ improving ad hydrogen bonds findings suggest fibril interactions enhanced rigidity embedded aβ demanding tasks close contact associated complex ad ), |
| status_str | publishedVersion |
| title | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations |
| title_full | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations |
| title_fullStr | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations |
| title_full_unstemmed | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations |
| title_short | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations |
| title_sort | A Small Molecule Impedes the Aβ<sub>1–42</sub> Tetramer Neurotoxicity by Preserving Membrane Integrity: Microsecond Multiscale Simulations |
| topic | Biophysics Biochemistry Medicine Cell Biology Neuroscience Pharmacology Immunology Computational Biology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Physical Sciences not elsewhere classified unrestricted conformational flexibility reduced conformational changes positively charged residues explicit solvent model economic burden worldwide bottom bilayer leaflet bilayer surface due bilayer hydrophobic region small molecule impedes mounting evidence envisages m30 molecules bind affected mice memory aa )/ coarse membrane phosphate groups membrane bilayer organization deep tetramer penetration conformational stable aβ preserving membrane integrity oligomers ’ interactions cg md simulations membrane bilayer termed m30 severely affected experimental evidence aβ molecule oligomer ’ alzheimer ’ dmpc bilayer μs aa vivo </ vitro </ tetramer structure tetramer penetrates tetramer neurotoxicity tetramer dissociation soluble aβ significantly perturb rigid structure recent trials observations support membrane contacts md simulations main hallmark main components insoluble aβ improving ad hydrogen bonds findings suggest fibril interactions enhanced rigidity embedded aβ demanding tasks close contact associated complex ad ), |