Arginine and disordered amyloid-β peptide structures: molecular level insights into the toxicity in Alzheimer's disease.

Recent studies present that the single arginine (R) residue in the sequence of Aβ42 adopts abundant β-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the Aβ assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of Aβ42 are poorly understood.

Structures and free energy landscapes of the A53T mutant-type α-synuclein protein and impact of A53T mutation on the structures of the wild-type α-synuclein protein with dynamics.

The A53T genetic missense mutation of the wild-type α-synuclein (αS) protein was initially identified in Greek and Italian families with familial Parkinson's disease. Detailed understanding of the structures and the changes induced in the wild-type αS structure by the A53T mutation, as well as establishing the direct relationships between the rapid conformational changes and free energy landscapes of these intrinsically disordered fibrillogenic proteins, helps to enhance our fundamental knowledge and to gain insights into the pathogenic mechanism of Parkinson's disease. We employed extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to determine the secondary and tertiary structural properties as well as the conformational free energy surfaces of the wild-type and A53T mutant-type αS proteins in an aqueous solution medium using both implicit and explicit water models.

The structures of the E22Δ mutant-type amyloid-β alloforms and the impact of E22Δ mutation on the structures of the wild-type amyloid-β alloforms.

Structural differences between the intrinsically disordered fibrillogenic wild-type Aβ40 and Aβ42 peptides are linked to Alzheimer's disease. Recently, the E22Δ genetic missense mutation was detected in patients exhibiting Alzheimer's-disease type dementia. However, detailed knowledge about the E22Δ mutant-type Aβ40 and Aβ42 alloform structures as well as the differences from the wild-type Aβ40 and Aβ42 alloform structures is currently lacking.

Structures of the E46K mutant-type α-synuclein protein and impact of E46K mutation on the structures of the wild-type α-synuclein protein.

The E46K genetic missense mutation of the wild-type α-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson's disease. Detailed understanding of the structures of the monomeric E46K mutant-type α-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type α-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson's disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment.

Structures and free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins with dynamics.

The genetic missense A30P mutation of the wild-type α-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations.

Probing and trapping a sensitive conformation: amyloid-β fibrils, oligomers, and dimers.

Alzheimer's disease (AD) is a devastating neurodegenerative disease with pathological misfolding of amyloid-β protein (Aβ). The recent interest in Aβ misfolding intermediates necessitates development of novel detection methods and ability to trap these intermediates. We speculated that two regions of Aβ may allow for detection of specific Aβ species: the N-terminal and 22-35, both likely important in oligomer interaction and formation.

Structures and free energy landscapes of aqueous zinc(II)-bound amyloid-β(1-40) and zinc(II)-bound amyloid-β(1-42) with dynamics.

Binding of divalent metal ions with intrinsically disordered fibrillogenic proteins, such as amyloid-β (Aβ), influences the aggregation process and the severity of neurodegenerative diseases. The Aβ monomers and oligomers are the building blocks of the aggregates. In this work, we report the structures and free energy landscapes of the monomeric zinc(II)-bound Aβ40 (Zn:Aβ40) and zinc(II)-bound Aβ42 (Zn:Aβ42) intrinsically disordered fibrillogenic metallopeptides in an aqueous solution by utilizing an approach that employs first principles calculations and parallel tempering molecular dynamics simulations.

Amyloid-β peptide structure in aqueous solution varies with fragment size.

Various fragment sizes of the amyloid-β (Aβ) peptide have been utilized to mimic the properties of the full-length Aβ peptide in solution. Among these smaller fragments, Aβ16 and Aβ28 have been investigated extensively. In this work, we report the structural and thermodynamic properties of the Aβ16, Aβ28, and Aβ42 peptides in an aqueous solution environment.