Early aggregation mechanism of Aβ16−22 revealed by Markov state models

Rahman, Mueed Ur; Song, Kaiyuan; Da, Lin-Tai; Chen, Haifeng

doi:10.1016/j.ijbiomac.2022.02.001

Cited by 6 publications

(3 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Elongation proceeds through the fusion of oligomers either at the extremities of a nascent amorphous protofibril or at multiple lateral surface points, reminiscent of secondary nucleation (surface-catalyzed) mechanism. 12 While most of the simulations computed free energy landscapes of the dominant oligomers, 8,13 the aggregation pathways, [14][15][16][17] the kinetic network analysis, [18][19][20] and the disconnectivity graphs 21 between different oligomers, a few studies focused on the potential of mean force (PMF) associated with the microscopic aggregation events, namely primary nucleation, fragmentation and surfacecatalyzed secondary nucleation, and fibril growth and depolymerization. [22][23][24][25][26][27] Notably, Monte Carlo simulations of a mesoscopic model with few degrees of freedom in implicit solvent 28 determined a PMF on the order of 7-10 kcal mol À1 for Aβ42 primary nucleation at concentrations varying between 60 μM and 4 mM.…”

Section: Introductionmentioning

confidence: 99%

Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

et al. 2023

View full text Add to dashboard Cite

Atomic characterization of large nonfibrillar aggregates of amyloid polypeptides cannot be determined by experimental means. Starting from β-rich aggregates of Y and elongated topologies predicted by coarse-grained simulations and consisting of more than 100 Aβ16-22 peptides, we performed atomistic molecular dynamics (MD), replica exchange with solute scaling (REST2), and umbrella sampling simulations using the CHARMM36m force field in explicit solvent. Here, we explored the dynamics within 3 μs, the free energy landscape, and the potential of mean force associated with either the unbinding of one single peptide in different configurations within the aggregate or fragmentation events of a large number of peptides. Within the time scale of MD and REST2, we find that the aggregates experience slow global conformational plasticity, and remain essentially random coil though we observe slow betastrand structuring with a dominance of antiparallel beta-sheets over parallel betasheets. Enhanced REST2 simulation is able to capture fragmentation events, and the free energy of fragmentation of a large block of peptides is found to be similar to the free energy associated with fibril depolymerization by one chain for longer Aβ sequences.

show abstract

Section: Introductionmentioning

confidence: 99%

Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Although the above crystal structure has revealed the importance of T758 in stabilizing the complex, the detailed mechanism of inhibitory effect on the filamin/integrin complex upon T758 phosphorylation at the atom level is still not fully understood. Markov state model (MSM), which is based on statistical models utilizing a pool of short-time molecular dynamics (MD) trajectories to explore the functional changes of conformation ensembles, − has been widely applied in the field of protein folding, − protein–DNA interactions, − and protein–protein interactions. , …”

Section: Introductionmentioning

confidence: 99%

Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model

Hong

Song

Rahman

et al. 2023

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Leukocyte adhesion deficiency-1 (LAD-1) disorder is a severe immunodeficiency syndrome caused by deficiency or mutation of β2 integrin. The phosphorylation on threonine 758 of β2 integrin acts as a molecular switch inhibiting the binding of filamin. However, the switch mechanism of site-specific phosphorylation at the atom level is still poorly understood. To resolve the regulation mechanism, all-atom molecular dynamics simulation and Markov state model were used to study the dynamic regulation pathway of phosphorylation. Wild type system possessed lower binding free energy and fewer number of states than the phosphorylated system. Both systems underwent local disorder-to-order conformation conversion when achieving steady states. To reach steady states, wild type adopted less number of transition paths/shortest path according to the transition path theory than the phosphorylated system. The underlying phosphorylated regulation pathway was from P1 to P0 and then P4 state, and the main driving force should be hydrogen bond and hydrophobic interaction disturbing the secondary structure of phosphorylated states. These studies will shed light on the pathogenesis of LAD-1 disease and lay a foundation for drug development.

show abstract

“…Although mechanistic insights are crude and lacking in experimental studies, previous in silico work, including molecular dynamics (MD) simulations, has proven to be a powerful tool in facilitating such discoveries. In particular, the development of enhanced sampling and analysis techniques enables the study of these systems, uncovering the mechanistic and kinetic importance of certain regions on Tau in the aggregation process, and guiding future therapeutic targets [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Investigating the Theranostic Potential of Graphene Quantum Dots in Alzheimer’s Disease

Walton-Raaby,

Woods,

Kalyaanamoorthy

2023

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is one of the leading causes of death worldwide, with no definitive diagnosis or known cure. The aggregation of Tau protein into neurofibrillary tangles (NFTs), which contain straight filaments (SFs) and paired helical filaments (PHFs), is a major hallmark of AD. Graphene quantum dots (GQDs) are a type of nanomaterial that combat many of the small-molecule therapeutic challenges in AD and have shown promise in similar pathologies. In this study, two sizes of GQDs, GQD7 and GQD28, were docked to various forms of Tau monomers, SFs, and PHFs. From the favorable docked poses, we simulated each system for at least 300 ns and calculated the free energies of binding. We observed a clear preference for GQD28 in the PHF6 (306VQIVYK311) pathological hexapeptide region of monomeric Tau, while GQD7 targeted both the PHF6 and PHF6* (275VQIINK280) pathological hexapeptide regions. In SFs, GQD28 had a high affinity for a binding site that is available in AD but not in other common tauopathies, while GQD7 behaved promiscuously. In PHFs, GQD28 interacted strongly near the protofibril interface at the putative disaggregation site for epigallocatechin-3-gallate, and GQD7 largely interacted with PHF6. Our analyses revealed several key GQD binding sites that may be used for detecting, preventing, and disassembling the Tau aggregates in AD.

show abstract

Early aggregation mechanism of Aβ16−22 revealed by Markov state models

Cited by 6 publications

References 104 publications

Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model

Investigating the Theranostic Potential of Graphene Quantum Dots in Alzheimer’s Disease

Contact Info

Product

Resources

About