Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model
| Autor: | Andrzej Kolinski, Anirban Banerji, Irina A. Buhimschi, Andrzej Kloczkowski, Maksim Kouza |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Amyloid beta-Peptides Chemistry Kinetics Protein Misfolding Disorder General Physics and Astronomy Molecular Dynamics Simulation Amyloid fibril Article Peptide Fragments Polymerization 03 medical and health sciences Molecular dynamics 030104 developmental biology Biochemistry Physical and Theoretical Chemistry Peptides Protein Binding |
| Popis: | Preeclampsia, a pregnancy-specific disorder, shares typical pathophysiological features with protein misfolding disorders including Alzheimer's disease. Characteristic for preeclampsia is the involvement of multiple proteins of which fragments of SERPINA1 and β-amyloid co-aggregate in urine and placenta of preeclamptic women. To explore the biophysical basis of this interaction, we investigated the multidimensional efficacy of the FVFLM sequence in SERPINA1, as a model inhibitory agent of β-amyloid aggregation. After studying the oligomerization of FVFLM peptides using all-atom molecular dynamics simulations with the GROMOS43a1 force field and explicit water, we report that FVFLM can aggregate and its aggregation is spontaneous with a remarkably faster rate than that recorded for KLVFF (aggregation “hot-spot” from β-amyloid). The fast kinetics of FVFLM aggregation was found to be driven primarily by core-like aromatic interactions originating from the anti-parallel orientation of complementarily uncharged strands. The conspicuously stable aggregation mechanism observed for FVFLM peptides is found not to conform to the popular 'dock-lock' scheme. We also found high propensity of FVFLM for KLVFF binding. When present, FVFLM disrupts the β-amyloid aggregation pathway and we propose that FVFLM-like peptides might be used to prevent the assembly of full-length Aβ or other pro-amyloidogenic peptides into amyloid fibrils. |
| Databáze: | OpenAIRE |
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