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

Abstract

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-β proteins, while the intracellular aggregates are formed from microtubule-binding tau proteins. The amyloid forming peptide sequences in the amyloid-β 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 β-sheet like secondary structures of sequences from amyloid-β 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 α-helix like secondary structure. For the parallel and anti-parallel dimer of KLVFFA, double well potentials were obtained with the minima corresponding to α-helix and β-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.

Keywords: Alzheimer’s disease; QM calculations; Tau protein; amyloid forming peptides; amyloid-β peptide; free energy calculations; umbrella sampling simulations.

Figure 1

The schematic represents of monomeric form of KLVFFA, with 5 ψ angles in total with one corresponding to each peptide bond. The red box indicates the location of different peptide bonds in the KLVFFA sequence.

Figure 2

Free energy profile of various conformations of KLVFFA. (a,b) helical and coil forms of monomer, (c,d) helical and β-sheet forms of Dimer(parallel form), (e,f) helical and β-sheet forms of Dimer (anti-parallel form).

Figure 3

Free energy profile of various conformations of QVEVKSEKLD and VQIVYKPVD respectively. (a,b) helical and β-sheet of QVEVKSEKLD, (c,d) helical and β-sheet of VQIVYKPVD.

Figure 4

Calculated total energy of conformations at different ψ angles using the M06-2X/6-31+G* level of theory for QVEVKSEKLD. (a) The secondary structure corresponds to the alpha helix dimer and (b) Beta-sheet dimer.

Figure 5

(a) Calculated total energy of conformations at different ψ angles using the PM7 level of theory for KLVFFA. (b) The helical conformation at first minimum (−60°) of KLVFFA.

Figure 6

(a,b) Calculated total energy of conformations at different ψ angles using the PM7 level of theory. (c,d) The secondary structure that corresponds to the first minima and second minima respectively.

Figure 7

(a) Free energy profile as a function of <ψ> for penta-alanine in monomeric and dimeric form from wham analysis (b) Energy profile as a function of <ψ> for monomeric form of penta-alanine using PM7 and M06-2X level of theory (c) energy profile as a function of <ψ> for dimeric form of penta-alanine using PM7 and M06-2X level of theory.

Figure 8

The representative configuration for penta-alanine monomer with (a) <ψ> = −60, (b) <ψ>=20, and (c) <ψ> = 80.