Related Experiment Video

Updated: Dec 8, 2025

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches

Published on: October 13, 2022

Impact of Mutations on the Conformational Transition from α-Helix to β-Sheet Structures in Arctic-Type Aβ₄₀: Insights

Rajneet Kaur Saini¹, Suniba Shuaib¹, Deepti Goyal¹

¹Department of Chemistry, Faculty of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib 140406, Punjab, India.

|September 21, 2020

Abstract:

The amyloid-β (Aβ) protein aggregation into toxic oligomers and fibrils has been recognized as a key player in the pathogenesis of Alzheimer's disease. Recent experiments reported that a double alanine mutation (L17A/F19A) in the central hydrophobic core (CHC) region of [G22]Aβ₄₀ (familial Arctic mutation) diminished the self-assembly propensity of [G22]Aβ₄₀. However, the molecular mechanism behind the decreased aggregation tendency of [A17/A19/G22]Aβ₄₀ is not well understood. Herein, we carried out molecular dynamics simulations to elucidate the structure and dynamics of [G22]Aβ₄₀ and [A17/A19/G22]Aβ₄₀. The results for the secondary structure analysis reveal a significantly increased amount of the helical content in the CHC and C-terminal region of [A17/A19/G22]Aβ₄₀ as compared to [G22]Aβ₄₀. The bending free-energy analysis of D23-K28 salt bridge suggests that the double alanine mutation in the CHC region of [G22]Aβ₄₀ has the potential to reduce the fibril formation rate by 0.57 times of [G22]Aβ₄₀. Unlike [G22]Aβ₄₀, [A17/A19/G22]Aβ₄₀ largely sampled helical conformation, as determined by the minimum energy conformations extracted from the free-energy landscape. The present study provided atomic level details into the experimentally observed diminished aggregation tendency of [A17/A19/G22]Aβ₄₀ as compared to [G22]Aβ₄₀.

More Related Videos

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Author Spotlight: In Silico Creation and Impact of Carbonylated Amino Acids on Protein Structure and Function

Author Spotlight: In Silico Creation and Impact of Carbonylated Amino Acids on Protein Structure and Function

Published on: April 26, 2024

Related Concept Videos

Protein Folding

Protein Folding

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...

Protein Folding

Protein Folding

Molecular Chaperones and Protein Folding

Molecular Chaperones and Protein Folding

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...

¹H NMR of Conformationally Flexible Molecules: Temporal Resolution

¹H NMR of Conformationally Flexible Molecules: Temporal Resolution

At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...

¹H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR

¹H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR

The axial and equatorial protons in cyclohexane can be distinguished by performing a variable-temperature NMR experiment. In this process, except for one proton, the remaining eleven protons are replaced by deuterium. The deuterium substitution avoids the possible peak splitting caused by the spin-spin coupling between the adjacent protons. The remaining proton flips between the axial and equatorial positions.

Amyloid Fibrils

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...

Articles linked to this work by shared authors, journal, and citation graph.

Macrocyclic peptides and peptidomimetics as modulators of protein-protein interactions.

RSC medicinal chemistry·2026

Leveraging molecular dynamics to unravel the inhibition mechanism of potential β-secretase (BACE1) inhibitors.

Physical chemistry chemical physics : PCCP·2026

Conjugation of Dietary Carnosine to Phe-Leu Dipeptide Affords a Potent Inhibitor of Multifaceted Aβ-Induced Neurotoxicity.

Bioconjugate chemistry·2026

Mechanistic insights into the inhibition of hIAPP fibrillation by amyloidogenic core-derived peptide NFGAILSS using computer simulations.

Physical chemistry chemical physics : PCCP·2026

Mutations in the Aβ42 Recognition Sequence KLVFF Afford New Pentapeptide Inhibitors of Aβ42 Fibrillation: Computation-Driven Rational Design and Experimental Validation.

The journal of physical chemistry. B·2026

Synergistic Effect of Mutations in the Amyloidogenic Core of Human Amylin (hAM) Affords a New Potent Inhibitor of hAM Fibrillation: Computational Design and Experimental Validation.

ACS chemical neuroscience·2026

See all related articles