Relationships between Mechanostability, Aggregation Rate and Binding Affinity of Peptides: Insights from All-ATOM Modeling in Explicit Solvent

Abstract

Fibril formation resulting from protein misfoding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite much progress in understanding the protein/peptide aggregation process, the factors governing aggregation rates and stability of oligomers/fibrils have not been fully understood. Studying the oligomerization of FVFLM peptides from the placenta of Preeclampsia patients and from using all-atom molecular dynamics simulations with GROMOS43a1 force field and explicit water, we show that fibril formation time (mechanical stability) strongly correlates with binding affinity. The faster fibril formation time (stronger mechanical stability) the stronger binding. The extent of superior mechanical stability/binding of FVFLM as compared to KLVFF, was quantified by subjecting both to steered molecular dynamics. The binding free energy of FVFLM and KLVFF systems, calculated from potential of mean force curve obtained through extensive umbrella sampling simulations, clearly established FVFLM as a better binder than KLVFF. Our study indicates that oligomer formation times are strongly correlated with binding energy, the faster the aggregation rate of peptide the stronger has been noted to be its mechanical stability and binding affinity.