Assessment of Amyloid Forming Tendency of Peptide Sequences from Amyloid Beta and Tau Proteins Using Force-Field, Semi-Empirical, and Density Functional Theory Calculations

A wide variety of neurodegenerative diseases are characterized by the accumulation of protein aggregates in intraneuronal or extraneuronal brain regions. In Alzheimer's disease (AD), the extracellular aggregates originate from amyloid-beta proteins, while the intracellular aggregates are formed from microtubule-binding tau proteins. The amyloid forming peptide sequences in the amyloid-beta peptides and tau proteins are responsible for aggregate formation. Experimental studies have until the date reported many of such amyloid forming peptide sequences in different proteins, however, there is still limited molecular level understanding about their tendency to form aggregates. In this study, we employed umbrella sampling simulations and subsequent electronic structure theory calculations in order to estimate the energy profiles for interconversion of the helix to beta-sheet like secondary structures of sequences from amyloid-beta protein (KLVFFA) and tau protein (QVEVKSEKLD and VQIVYKPVD). The study also included a poly-alanine sequence as a reference system. The calculated force-field based free energy profiles predicted a flat minimum for monomers of sequences from amyloid and tau proteins corresponding to an alpha-helix like secondary structure. For the parallel and anti-parallel dimer of KLVFFA, double well potentials were obtained with the minima corresponding to alpha-helix and beta-sheet like secondary structures. A similar double well-like potential has been found for dimeric forms for the sequences from tau fibril. Complementary semi-empirical and density functional theory calculations displayed similar trends, validating the force-field based free energy profiles obtained for these systems.

Automated summary

The study utilized umbrella sampling simulations and electronic structure theory calculations to analyze the aggregation process of amyloid and tau protein sequences, revealing that monomers of these sequences exhibit alpha-helix like secondary structures, while dimers show double well potentials corresponding to alpha-helix and beta-sheet like secondary structures. Complementary semi-empirical and density functional theory calculations validated the force-field based free energy profiles obtained for these systems.