Interactions of a multifunctional di-triazole derivative with Alzheimer's Aβ42 monomer and Aβ42 protofibril: a systematic molecular dynamics study

2020 ◽  
Vol 22 (3) ◽  
pp. 1543-1556 ◽  
Author(s):  
Anupamjeet Kaur ◽  
Suniba Shuaib ◽  
Deepti Goyal ◽  
Bhupesh Goyal
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Triazole Derivative ◽  
Helix Conformation ◽  
Α Helix ◽  
Dynamics Simulations

The molecular dynamics simulations results highlighted that the multi-target-directed ligand 6n stabilizes the native α-helix conformation of the Aβ42 monomer and induces a sizable destabilization in the Aβ42 protofibril structure.

scholarly journals Unfolding of α-helical 20-residue poly-glutamic acid analyzed by multiple runs of canonical molecular dynamics simulations

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4769 ◽  
Author(s):  
Naoki Ogasawara ◽  
Kota Kasahara ◽  
Ryosuke Iwai ◽  
Takuya Takahashi
Keyword(s):  
Molecular Dynamics ◽  
Glutamic Acid ◽  
Molecular Dynamics Simulations ◽  
Helical Conformation ◽  
Short Peptides ◽  
Computational Studies ◽  
Middle Region ◽  
Helix Conformation ◽  
Α Helix ◽  
Dynamics Simulations

Elucidating the molecular mechanism of helix–coil transitions of short peptides is a long-standing conundrum in physical chemistry. Although the helix–coil transitions of poly-glutamic acid (PGA) have been extensively studied, the molecular details of its unfolding process still remain unclear. We performed all-atom canonical molecular dynamics simulations for a 20-residue PGA, over a total of 19 μs, in order to investigate its helix-unfolding processes in atomic resolution. Among the 28 simulations, starting with the α-helical conformation, all showed an unfolding process triggered by the unwinding of terminal residues, rather than by kinking and unwinding of the middle region of the chain. The helix–coil–helix conformation which is speculated by the previous experiments was not observed. Upon comparison between the N- and C-termini, the latter tended to be unstable and easily unfolded. While the probabilities of helix elongation were almost the same among the N-terminal, middle, and C-terminal regions of the chain, unwinding of the helix was enriched at the C-terminal region. The turn and 310-helix conformations were kinetic intermediates in the formation and deformation of α-helix, consistent with the previous computational studies for Ala-based peptides.

An α-helix mimetic oligopyridylamide, ADH-31, modulates Aβ42 monomer aggregation and destabilizes protofibril structures: insights from molecular dynamics simulations

2020 ◽  
Vol 22 (48) ◽  
pp. 28055-28073
Author(s):  
Anupamjeet Kaur ◽  
Deepti Goyal ◽  
Bhupesh Goyal
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Helical Conformation ◽  
Aβ Peptide ◽  
Α Helix ◽  
Dynamics Simulations

The molecular dynamics simulations highlighted that ADH-31 inhibited Aβ42 aggregation by constraining Aβ peptide into helical conformation and destabilized Aβ42 trimer as well as protofibril structures.

Activation helix orientation of the estrogen receptor is mediated by receptor dimerization: evidence from molecular dynamics simulations

2015 ◽  
Vol 17 (20) ◽  
pp. 13403-13420 ◽  
Author(s):  
Filip Fratev
Keyword(s):  
Molecular Dynamics ◽  
Estrogen Receptor ◽  
Molecular Dynamics Simulations ◽  
Dimer Formation ◽  
Receptor Dimerization ◽  
Helix 12 ◽  
Conformational Landscape ◽  
Helix Conformation ◽  
Helix Orientation ◽  
Dynamics Simulations

ERα dimer formation reshapes the helix 12 conformational landscape and is a leading factor for the activation helix conformation.

scholarly journals Conserved α-helix-3 is crucial for structure and functions of Rad6 E2 ubiquitin-conjugating enzymes

2021 ◽  
Author(s):  
Prakash K. Shukla ◽  
Dhiraj Sinha ◽  
Andrew M. Leng ◽  
Jesse E. Bissell ◽  
Shravya Thatipamula ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Biological Functions ◽  
Conjugating Enzymes ◽  
Α Helix ◽  
Dynamics Simulations ◽  
Ubiquitin Conjugating Enzymes ◽  
Structure And Activity

AbstractRad6, an E2 ubiquitin-conjugating enzyme conserved from yeast to humans, functions in transcription, genome maintenance and proteostasis. The contributions of many conserved secondary structures of Rad6 and its human homologs UBE2A and UBE2B to their biological functions are not understood. A mutant RAD6 allele with a missense substitution at alanine-126 (A126) of α-helix-3 that causes defects in telomeric gene silencing, DNA repair and protein degradation was reported over two decades ago. Here, using a combination of genetics, biochemical, biophysical, and computational approaches, we discovered that α-helix-3 A126 mutations compromise the ability of Rad6 to ubiquitinate target proteins without disrupting interactions with partner E3 ubiquitin-ligases that are required for their various biological functions in vivo. Explaining the defective in vitro or in vivo ubiquitination activities, molecular dynamics simulations and NMR showed that α-helix-3 A126 mutations cause local disorder of the catalytic pocket of Rad6, and also disorganize the global structure of the protein to decrease its stability in vivo. We further demonstrate that α-helix-3 A126 mutations deform the structures of UBE2A and UBE2B, the human Rad6 homologs, and compromise the in vitro ubiquitination activity and folding of UBE2B. Molecular dynamics simulations and circular dichroism spectroscopy along with functional studies further revealed that cancer-associated mutations in α-helix-3 of UBE2A or UBE2B alter both structure and activity, providing an explanation for their pathogenicity. Overall, our studies reveal that the conserved α-helix-3 is a crucial structural constituent that controls the organization of catalytic pockets and biological functions of the Rad6-family E2 ubiquitin-conjugating enzymes.HighlightsContributions of the conserved α-helix-3 to the functions of E2 enzymes is not known.Mutations in alanine-126 of α-helix-3 impair in vitro enzymatic activity and in vivo biological functions of Rad6.Mutations in alanine-126 of α-helix-3 disorganize local or global protein structure, compromise folding or stability, and impair the catalytic activities of yeast Rad6 and its human homologs UBE2A and UBE2B.Cancer-associated mutations in α-helix-3 of human UBE2A or UBE2B alter protein flexibility, structure, and activity.α-helix-3 is a key structural component of yeast and human Rad6 E2 ubiquitin-conjugating enzymes.

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