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

Charuvaka Muvva,Natarajan Arul Murugan,Venkatesan Subramanian

doi:10.3390/ijms22063244

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.

Highlights

Protein aggregation is essentially a self-association process in which many identical peptides form higher-order conglomerates of low solubility that eventually precipitate [1,2,3]
To further validate the free energy profiles obtained from the force-field approach, PM7 level semi-empirical calculations and density functional theory calculations at M06-2X/6-31+G* level of theory were carried out
The obtained energy profiles reveal that the KLVFFA and VQIVYKPVD sequences exist preferentially in helical form when they are in the monomeric state, while helical and β-sheet like secondary structures are predominant for the dimeric state

Summary

Introduction

Protein aggregation is essentially a self-association process in which many identical peptides form higher-order conglomerates of low solubility that eventually precipitate [1,2,3]. Protein aggregation underlies the pathogenesis of several human neurodegenerative diseases, such as Alzheimer’s (AD) [4,5], Parkinson’s (PD) [6,7], Huntington’s diseases (HD) [8,9], prion [10,11], Amyotrophic Lateral Sclerosis (ALS) [12,13], and Frontotemporal lobar degeneration (FTLD) [14] All of these diseases have common cellular and molecular mechanisms including protein aggregation and self-amplifying inflammatory processes. Källberg et al suggested that when the Aβ peptide residues 14-23 are removed or changed to a non-discordant sequence, fibrils are no longer formed [22] This suggests that there exist certain amyloid forming sequences, which are responsible for protein misfolding and subsequent aggregation. The replica-exchange molecular dynamics (REMD) simulations conducted by Davis et al reported that in presence of lipid bilayer, the abeta monomer did not convert into beta-sheet suggesting that beta-sheet formation is due to protein-protein interaction [26]

Methods

Results

Conclusion