title: 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 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.
authors.affiliation: Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland. mkouza@chem.uw.edu.pl and Nationwide Children's Hospital, Battelle Center for Mathematical Medicine, Columbus, OH 43215, USA.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-1704-9797
authors.initials: M
authors.lastname: Kouza
authors.affiliation: Nationwide Children's Hospital, Battelle Center for Mathematical Medicine, Columbus, OH 43215, USA.
authors.forename: A
authors.initials: A
authors.lastname: Banerji
authors.affiliation: Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland. mkouza@chem.uw.edu.pl.
authors.forename: A
authors.initials: A
authors.lastname: Kolinski
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, USA and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Buhimschi
authors.affiliation: Nationwide Children's Hospital, Battelle Center for Mathematical Medicine, Columbus, OH 43215, USA and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kloczkowski
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D058105:Polymerization; D011485:Protein Binding
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C529399:amyloid beta-protein (16-20)