Promotion and Inhibition of Amyloid-β Peptide Aggregation: Molecular Dynamics Studies

Aggregates of amyloid-β (Aβ) peptides are known to be related to Alzheimer’s disease. Their aggregation is enhanced at hydrophilic–hydrophobic interfaces, such as a cell membrane surface and air-water interface, and is inhibited by polyphenols, such as myricetin and rosmarinic acid. We review molecular dynamics (MD) simulation approaches of a full-length Aβ peptide, Aβ40, and Aβ(16–22) fragments in these environments. Since these peptides have both hydrophilic and hydrophobic amino acid residues, they tend to exist at the interfaces. The high concentration of the peptides accelerates the aggregation there. In addition, Aβ40 forms a β-hairpin structure, and this structure accelerates the aggregation. We also describe the inhibition mechanism of the Aβ(16–22) aggregation by polyphenols. The aggregation of Aβ(16–22) fragments is caused mainly by the electrostatic attraction between charged amino acid residues known as Lys16 and Glu22. Since polyphenols form hydrogen bonds between their hydroxy and carboxyl groups and these charged amino acid residues, they inhibit the aggregation.

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Using Small Peptide Segments of Amyloid-β and Humanin to Examine their Physical Interactions

Protein and Peptide Letters ◽

10.2174/0929866526666190405122117 ◽

2019 ◽

Vol 26 (7) ◽

pp. 502-511 ◽

Cited By ~ 3

Author(s):

Deborah L. Heyl ◽

Brandon Iwaniec ◽

Daniel Esckilsen ◽

Deanna Price ◽

Prathyusha Guttikonda ◽

...

Keyword(s):

Amino Acid ◽

Amyloid Fibrils ◽

Amyloid Β ◽

Full Length ◽

Binding Kinetics ◽

Amino Acid Residues ◽

Aβ Peptides ◽

Physical Interactions ◽

Peptide Segments ◽

Kinetics Of

Background: Amyloid fibrils in Alzheimer’s disease are composed of amyloid-β (Aβ) peptides of variant lengths. Humanin (HN), a 24 amino acid residue neuroprotective peptide, is known to interact with the predominant Aβ isoform in the brain, Aβ (1-40). Methods: Here, we constructed smaller segments of Aβ and HN and identified residues in HN important for both HN-HN and HN-Aβ interactions. Peptides corresponding to amino acid residues 5- 15 of HN, HN (5-15), HN (5-15, L11S), where Leu11 was replaced with Ser, and residues 17-28 of Aβ, Aβ (17-28), were synthesized and tested for their ability to block formation of the complex between HN and Aβ (1-40). Results: Co-immunoprecipitation and binding kinetics showed that HN (5-15) was more efficient at blocking the complex between HN and Aβ (1-40) than either HN (5-15, L11S) or Aβ (17-28). Binding kinetics of these smaller peptides with either full-length HN or Aβ (1-40) showed that HN (5- 15) was able to bind either Aβ (1-40) or HN more efficiently than HN (5-15, L11S) or Aβ (17-28). Compared to full-length HN, however, HN (5-15) bound Aβ (1-40) with a weaker affinity suggesting that while HN (5-15) binds Aβ, other residues in the full length HN peptide are necessary for maximum interactions. Conclusion: L11 was more important for interactions with Aβ (1-40) than with HN. Aβ (17-28) was relatively ineffective at binding to either Aβ (1-40) or HN. Moreover, HN, and the smaller HN (5-15), HN (5-15 L11S), and Aβ (17-28) peptides, had different effects on regulating Aβ (1-40) aggregation kinetics.

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Investigation of the interaction of amyloid β peptide (11–42) oligomers with a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane using molecular dynamics simulation

Physical Chemistry Chemical Physics ◽

10.1039/c7cp07148e ◽

2018 ◽

Vol 20 (10) ◽

pp. 6817-6829 ◽

Cited By ~ 14

Author(s):

Ning Xiang ◽

Yuan Lyu ◽

Xiao Zhu ◽

Ganesan Narsimhan

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Pore Formation ◽

Amyloid Β ◽

Dynamics Simulation ◽

Amyloid Β Peptide ◽

Aβ Oligomers ◽

Aβ Peptides ◽

Amyloid Aβ ◽

Β Amyloid

The mechanism of pore formation in model neural cell membranes by β amyloid (Aβ) peptides was investigated using molecular dynamics simulation which indicated that Aβ oligomers of size equal or greater than 3 has a higher tendency for pore formation than monomers and that cholesterol tends to retard Aβ binding and insertion into the membrane.

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Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

Current Computer - Aided Drug Design ◽

10.2174/1573409915666190708103132 ◽

2020 ◽

Vol 16 (4) ◽

pp. 451-459 ◽

Cited By ~ 1

Author(s):

Fortunatus C. Ezebuo ◽

Ikemefuna C. Uzochukwu

Keyword(s):

Molecular Dynamics ◽

Amino Acid ◽

Binding Energy ◽

Binding Site ◽

Conformational Dynamics ◽

Side Chain ◽

Amino Acid Residues ◽

Conformational Selection ◽

Hybrid Mechanism ◽

Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

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Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures

Scientific Reports ◽

10.1038/s41598-020-77808-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Felipe P. Perez ◽

Bryan Maloney ◽

Nipun Chopra ◽

Jorge J. Morisaki ◽

Debomoy K. Lahiri

Keyword(s):

Electromagnetic Field ◽

Late Onset ◽

Amyloid Β ◽

Clinical Settings ◽

Amyloid Β Peptide ◽

Field Stimulation ◽

Amino Acid Residues ◽

Hyperphosphorylated Tau Protein ◽

Magnetic Resonance Imaging Mri

AbstractLate Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.

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New CHARMM force field parameters for dehydrated amino acid residues, the key to lantibiotic molecular dynamics simulations

RSC Advances ◽

10.1039/c4ra09897h ◽

2014 ◽

Vol 4 (89) ◽

pp. 48621-48631 ◽

Cited By ~ 9

Author(s):

Eleanor R. Turpin ◽

Sam Mulholland ◽

Andrew M. Teale ◽

Boyan B. Bonev ◽

Jonathan D. Hirst

Keyword(s):

Molecular Dynamics ◽

Amino Acid ◽

Force Field ◽

Molecular Dynamics Simulations ◽

Amino Acid Residues ◽

Charmm Force Field ◽

Force Field Parameters ◽

Dynamics Simulations

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A theoretical study on the molecular determinants of the affibody protein ZAβ3bound to an amyloid β peptide

Physical Chemistry Chemical Physics ◽

10.1039/c5cp00615e ◽

2015 ◽

Vol 17 (26) ◽

pp. 16886-16893 ◽

Cited By ~ 3

Author(s):

Xu Wang ◽

Xianqiang Sun ◽

Guanglin Kuang ◽

Hans Ågren ◽

Yaoquan Tu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Theoretical Study ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Aβ Peptides ◽

Molecular Determinants

The investigation of the (ZAβ3)2:Aβ complex highlights the energetic contribution of affibody residues to the binding with alzheimer's disease associated Aβ peptides.

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ReaxFF-based molecular dynamics simulation of the interaction between plasma ROS and the receptor-binding domain of the spike protein in the capsid protein of SARS-CoV-2

Journal of Physics D Applied Physics ◽

10.1088/1361-6463/ac360e ◽

2021 ◽

Author(s):

Huichao Wang ◽

Tong Zhao ◽

Shuhui Yang ◽

Liang Zou ◽

Xiaolong Wang ◽

...

Keyword(s):

Molecular Dynamics ◽

Amino Acid ◽

Capsid Protein ◽

Receptor Binding ◽

Hydrogen Abstraction ◽

Binding Domain ◽

Spike Protein ◽

Receptor Binding Domain ◽

Amino Acid Residues ◽

Global Epidemic

Abstract Under the severe situation of the current global epidemic, researchers have been working hard to find a reliable way to suppress the infection of the virus and prevent the spread of the epidemic. Studies have shown that the recognition and binding of human angiotensin-converting enzyme 2 (ACE2) by the receptor-binding domain (BRD) of spike protein on the surface of SARS-CoV-2 is a crucial step for SARS-CoV-2 to invade human receptor cells, and blocking this process can inhibit the virus from invading human normal cells. Plasma treatment can disrupt the structure of the RBD and effectively block the binding process. However, the mechanism by which plasma blocks the recognition and binding between the two is not clear. In this study, reaction process between reactive oxygen species (ROS) in plasma and the molecular model of RBD was simulated using a reactive molecular dynamics method. The results showed that the destruction of RBD molecule by ROS was triggered by hydrogen abstraction reactions. O and OH abstracted H atoms from RBD, while the H atoms of H2O2 and HO2 were abstracted by RBD. The hydrogen abstraction resulted in the breakage of C-H, N-H, O-H and C=O bonds and the formation of C=C, C=N bonds. The addition reaction of OH increased the number of O-H bonds and caused the formation of C-O, N-O and O-H bonds. The dissociation of N-H bonds led to the destruction of the original structure of peptide bonds and amino acid residues, change the type of amino acid residues, and caused the conversion of N-C and N=C, C=O and C-O. The simulation partially elucidated the microscopic mechanism of the interaction between ROS in plasma and the capsid protein of SARS-CoV-2, providing theoretical support for the control of SARS-CoV-2 infection by plasma, a contribution to overcoming the global epidemic problem.

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Destabilization of Alzheimer’s Aβ42 protofibrils with acyclovir, carmustine, curcumin, and tetracycline: Insights from molecular dynamics simulations

New Journal of Chemistry ◽

10.1039/d1nj04453b ◽

2021 ◽

Author(s):

Ishrat Jahan ◽

Shahid M Nayeem

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Dynamics ◽

Neurodegenerative Diseases ◽

Molecular Dynamics Simulations ◽

Amyloid Β ◽

Neural Tissue ◽

Amyloid Β Peptide ◽

Characteristic Symptom ◽

Dynamics Simulations

One of the most common dementia among neurodegenerative diseases is Alzheimer’s disease (AD). The characteristic symptom of AD is the deposition and aggregation of amyloid-β-peptide in the neural tissue. A...

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