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Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model.

ABSTRACT: 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 ?-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 ?-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 ?-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 ?-amyloid aggregation pathway and we propose that FVFLM-like peptides might be used to prevent the assembly of full-length A? or other pro-amyloidogenic peptides into amyloid fibrils.

SUBMITTER: Kouza M

PROVIDER: S-EPMC5305032 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model.

Kouza M M Banerji A A Kolinski A A Buhimschi I A IA Kloczkowski A A

Physical chemistry chemical physics : PCCP 20170101 4

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-amyl ...[more]

PMID: 28079198

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Dataset Information

Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model.

Publications

Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model.

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