Molecular Mechanisms of Cryoprotection in Aqueous Proline:  Light Scattering and Molecular Dynamics Simulations

2008 ◽  
Vol 112 (14) ◽  
pp. 4290-4297 ◽  
Author(s):  
R. Z. Troitzsch ◽  
H. Vass ◽  
W. J. Hossack ◽  
G. J. Martyna ◽  
J. Crain
Keyword(s):  
Molecular Dynamics ◽  
Light Scattering ◽  
Molecular Dynamics Simulations ◽  
Molecular Mechanisms ◽  
Dynamics Simulations

‘Piperazining’ the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib

2019 ◽  
Vol 11 (18) ◽  
pp. 2365-2380
Author(s):  
Aimen K Aljoundi ◽  
Clement Agoni ◽  
Fisayo A Olotu ◽  
Mahmoud ES Soliman
Keyword(s):  
Molecular Dynamics ◽  
B Cell ◽  
Molecular Dynamics Simulations ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dynamics Simulation ◽  
Large B Cell Lymphoma ◽  
Dynamics Simulations ◽  
Large B Cell

Aim: Blocking oncogenic signaling of B-cell receptor (BCR) has been explored as a viable strategy in the treatment of diffuse large B-cell lymphoma. Masitinib is shown to multitarget LYN, FYN and BLK kinases that propagate BCR signals to downstream effectors. However, the molecular mechanisms of its selectivity and pan-inhibition remain elusive. Materials & methods: This study therefore employed molecular dynamics simulations coupled with advanced post-molecular dynamics simulation techniques to unravel the structural mechanisms that inform the reported multitargeting ability of masitinib. Results: Molecular dynamics simulations revealed initial selective targeting of catalytic residues (Asp334/Glu335 – LYN; Asp130/Asp148/Glu54 – FYN; Asp89 – BLK) by masitinib, with high-affinity interactions via its piperazine ring at the entrance of the ATP-binding pockets, before systematic access into the hydrophobic deep pocket grooves. Conclusion: Identification of these ‘gatekeeper’ residues could open up a novel paradigm of structure-based design of highly selective pan-inhibitors of BCR signaling in the treatment of diffuse large B-cell lymphoma.

scholarly journals Molecular dynamics simulations of the interaction of wild type and mutant human CYP2J2 with polyunsaturated fatty acids

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
K. K. Abelak ◽  
D. Bishop-Bailey ◽  
I. Nobeli
Keyword(s):  
Molecular Dynamics ◽  
Arachidonic Acid ◽  
Molecular Dynamics Simulations ◽  
Molecular Mechanisms ◽  
Homology Model ◽  
Cytochrome P450 Enzyme ◽  
Wild Type ◽  
Substrate Preferences ◽  
P450 Enzyme ◽  
Dynamics Simulations

Abstract Objectives The data presented here is part of a study that was aimed at characterizing the molecular mechanisms of polyunsaturated fatty acid metabolism by CYP2J2, the main cytochrome P450 enzyme active in the human cardiovasculature. This part comprises the molecular dynamics simulations of the binding of three eicosanoid substrates to wild type and mutant forms of the enzyme. These simulations were carried out with the aim of dissecting the importance of individual residues in the active site and the roles they might play in dictating the binding and catalytic specificity exhibited by CYP2J2. Data description The data comprise: (a) a new homology model of CYP2J2, (b) a number of predicted low-energy complexes of CYP2J2 with arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, produced with molecular docking and (c) a series of molecular dynamics simulations of the wild type and four mutants interacting with arachidonic acid as well as simulations of the wild type interacting with the two other eicosanoid ligands. The simulations may be helpful in identifying the determinants of substrate specificity of this enzyme and in unraveling the role of individual mutations on its function. They may also help guide the generation of mutants with altered substrate preferences.

scholarly journals Aggregation of Aβ40/42 chains in the presence of cyclic neuropeptides investigated by molecular dynamics simulations

2021 ◽  
Vol 17 (3) ◽  
pp. e1008771
Author(s):  
Min Wu ◽  
Lyudmyla Dorosh ◽  
Gerold Schmitt-Ulms ◽  
Holger Wille ◽  
Maria Stepanova
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Cyclic Peptides ◽  
Molecular Mechanisms ◽  
Surface Effect ◽  
Early Stage ◽  
Aβ Peptides ◽  
Hydrophobic Residues ◽  
Dynamics Simulations

Alzheimer’s disease is associated with the formation of toxic aggregates of amyloid beta (Aβ) peptides. Despite tremendous efforts, our understanding of the molecular mechanisms of aggregation, as well as cofactors that might influence it, remains incomplete. The small cyclic neuropeptide somatostatin-14 (SST14) was recently found to be the most selectively enriched protein in human frontal lobe extracts that binds Aβ42 aggregates. Furthermore, SST14’s presence was also found to promote the formation of toxic Aβ42 oligomers in vitro. In order to elucidate how SST14 influences the onset of Aβ oligomerization, we performed all-atom molecular dynamics simulations of model mixtures of Aβ42 or Aβ40 peptides with SST14 molecules and analyzed the structure and dynamics of early-stage aggregates. For comparison we also analyzed the aggregation of Aβ42 in the presence of arginine vasopressin (AVP), a different cyclic neuropeptide. We observed the formation of self-assembled aggregates containing the Aβ chains and small cyclic peptides in all mixtures of Aβ42–SST14, Aβ42–AVP, and Aβ40–SST14. The Aβ42–SST14 mixtures were found to develop compact, dynamically stable, but small aggregates with the highest exposure of hydrophobic residues to the solvent. Differences in the morphology and dynamics of aggregates that comprise SST14 or AVP appear to reflect distinct (1) regions of the Aβ chains they interact with; (2) the propensities to engage in hydrogen bonds with Aβ peptides; and (3) solvent exposures of hydrophilic and hydrophobic groups. The presence of SST14 was found to impede aggregation in the Aβ42–SST14 system despite a high hydrophobicity, producing a stronger “sticky surface” effect in the aggregates at the onset of Aβ42–SST14 oligomerization.

scholarly journals Aggregation behavior of amphiphilic cyclodextrins in a nonpolar solvent: evidence of large-scale structures by atomistic molecular dynamics simulations and solution studies

2016 ◽  
Vol 12 ◽  
pp. 73-80 ◽  
Author(s):  
Giuseppina Raffaini ◽  
Fabio Ganazzoli ◽  
Antonino Mazzaglia
Keyword(s):  
Molecular Dynamics ◽  
Light Scattering ◽  
Dynamic Light Scattering ◽  
Molecular Dynamics Simulations ◽  
Large Scale ◽  
Large Scale Structures ◽  
Modified Cyclodextrins ◽  
Solution Studies ◽  
Dynamics Simulations ◽  
Supramolecular Aggregates

Chemically modified cyclodextrins carrying both hydrophobic and hydrophilic substituents may form supramolecular aggregates or nanostructures of great interest. These systems have been usually investigated and characterized in water for their potential use as nanocarriers for drug delivery, but they can also aggregate in apolar solvents, as shown in the present paper through atomistic molecular dynamics simulations and dynamic light scattering measurements. The simulations, carried out with a large number of molecules in vacuo adopting an unbiased bottom-up approach, suggest the formation of bidimensional structures with characteristic length scales of the order of 10 nm, although some of these sizes are possibly affected by the assumed periodicity of the simulation cell, in particular at longer lengths. In any case, these nanostructures are stable at least from the kinetic viewpoint for relatively long times thanks to the large number of intermolecular interactions of dipolar and dispersive nature. The dynamic light scattering experiments indicate the presence of aggregates with a hydrodynamic radius of the order of 80 nm and a relatively modest polydispersity, even though smaller nanometer-sized aggregates cannot be fully ruled out. Taken together, these simulation and experimental results indicate that amphiphilically modified cyclodextrins do also form large-scale nanoaggregates even in apolar solvents.

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