Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

Abstract

Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and efficient drug design studies.

Effect of ferric citrate on amyloid‐beta peptides behavior

“…To better understand the dynamics of the iron complexation and the local environmental changes at N‐terminal region, we studied the intrinsic fluorescence of Tyrosine in position 10. The Tyrosine in the N‐terminal region of Aβ1–42 is reported to be active toward iron, zinc and copper binding . Moreover, the interactions with ligands at Tyr10 are proposed neurotoxic or neuroprotective because they influence the mechanisms of aggregation and the kinetics of Aβ1–42 .…”

“…The Tyrosine in the Nterminal region of Ab1-42 is reported to be active toward iron, zinc and copper binding. [67] Moreover, the interactions with ligands at Tyr10 are proposed neurotoxic or neuroprotective because they influence the mechanisms of aggregation and the kinetics of Ab1-42. [68][69][70] We have shown in Figure 9, the appearance of the Tyrosinate peak at about 345 nm with the Ab aggregation.…”

Salt-bridge Dynamics in Intrinsically Disordered Proteins: A trade-off between electrostatic interactions and structural flexibility

“…Design of salt-bridge mutants in Aß 42 ). The mutationapproach, implemented to study IDPs, has traditionally been devoted towards exploring their molecular evolution [74] and their pathological features [75]. In fact, there exists a good volume of literature on mutations performed on Aß 42 itself [76][77][78][79][80][81][82][83], designed to be located on the N-terminus and the middle part of the protein chain.…”

The Interaction of Curcumin and Rosmarinic Acid with Non‐Amyloid‐Component Domain of Alpha‐Synuclein: A Molecular Dynamics Study

“…The considered systems have been composed to form 5 separated chains of the NAC domain that includes the absolutely hydrophobic 61–95 residues and is involved in protein aggregation; we called it 5mer, with 10 and 20 CUR and RA molecules and a 5mer system without any ligand. The protein‐ligand interactions have been widely studied according to the mechanical and energetic viewpoints with the help of classical molecular dynamics (MD) simulations . In this work, along with the MD based analysis, the binding free energy for AS‐CUR and AS‐RA was calculated by the molecular mechanics Poisson‐Boltzmann Surface Area (MM‐PBSA) computations.…”

“…The protein-ligand interactions have been widely studied according to the mechanical and energetic viewpoints with the help of classical molecular dynamics (MD) simulations. [15][16][17] In this work, along with the MD based analysis, the binding free energy for AS-CUR and AS-RA was calculated by the molecular mechanics Poisson-Boltzmann Surface Area (MM-PBSA) computations. Furthermore, we studied the binding strength of the considered compounds and consequently, their inhibition competence in the AS aggregation process.…”