Computational Characterization of Oligomerization of FVFLM Peptide and its Ability to Inhibit Beta Amyloid Aggregation

Abstract

Preeclampsia, a pregnancy-specific disorder, shares typical pathophysiological features with protein misfolding disorders including Alzheimer's disease1. 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. This work explores the biophysical basis of this interaction by investigating the multidimensional efficacy of the FVFLM sequence in SERPINA1, as a model inhibitory agent of β-amyloid aggregation. Several algorithms predict FVFLM peptide as being a highly amyloidogenic2,3. 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 population of fibril-prone conformations in the monomeric state of KLVFF was found to be lower than FVFLM indicating the faster aggregation process of FVFLM4. 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. We also demonstrate a 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.1. Buhimschi, I.A. et al. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Science translational medicine6, 245ra292 (2014).2. Zambrano, R. et al. AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures. Nucleic Acids Res (2015).3. Kouza, M., Faraggi, E., Kolinski, A. & Kloczkowski, A. in Prediction of Protein Secondary Structure, Vol. 1484. (eds. Y. Zhou, A. Kloczkowski, E. Faraggi & Y. Yang) 7-24 (Humana Press, New York; 2016).4. Nam, H.B., Kouza, M., Hoang, Z. & Li, M.S. Relationship between population of the fibril-prone conformation in the monomeric state and oligomer formation times of peptides: Insights from all-atom simulations. J Chem Phys 132, 165104 (2010)