Exploring the Stability of Inhibitor Binding to SIK2 Using Molecular Dynamics Simulation and Binding Free Energy Calculation

2021 ◽  
Author(s):  
Mingsong Shi ◽  
Min Zhao ◽  
Lun Wang ◽  
Kongjun Liu ◽  
Penghui Li ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Inhibitor Binding ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Biological Phenomena ◽  
Dependent Protein ◽  
The Stability

Salt inducible kinase 2 (SIK2) is a calcium/calmodulin-dependent protein kinase-like kinase that is implicated in a variety of biological phenomena, including cellular metabolism, growth, and apoptosis. SIK2 is the key...

scholarly journals Hydrogen Bond Stability of Quinazoline Derivatives Compounds in Complex against EGFR using Molecular Dynamics Simulation

2019 ◽  
Vol 19 (2) ◽  
pp. 461
Author(s):  
Herlina Rasyid ◽  
Bambang Purwono ◽  
Thomas S Hofer ◽  
Harno Dwi Pranowo
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Inhibition Mechanism ◽  
Energy Calculation ◽  
Protein Receptor ◽  
The Stability

Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.

scholarly journals Effect of pH on the structure, function, and stability of human calcium/calmodulin-dependent protein kinase IV: combined spectroscopic and MD simulation studies

2016 ◽  
Vol 94 (3) ◽  
pp. 221-228 ◽  
Author(s):  
Huma Naz ◽  
Mohd. Shahbaaz ◽  
Krishna Bisetty ◽  
Asimul Islam ◽  
Faizan Ahmad ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Protein Kinase ◽  
Dynamics Simulation ◽  
Dimensional Structure ◽  
Spectroscopic Techniques ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Structural And Functional Properties ◽  
Dependent Protein ◽  
Ph Conditions

Human calcium/calmodulin-dependent protein kinase IV (CAMKIV) is a member of Ser/Thr protein kinase family. It is regulated by the calcium–calmodulin dependent signal through a secondary messenger, Ca2+, which leads to the activation of its autoinhibited form. The over-expression and mutation in CAMKIV as well as change in Ca2+ concentration is often associated with numerous neurodegenerative diseases and cancers. We have successfully cloned, expressed, and purified a functionally active kinase domain of human CAMKIV. To observe the effect of different pH conditions on the structural and functional properties of CAMKIV, we have used spectroscopic techniques such as circular diachroism (CD) absorbance and fluorescence. We have observed that within the pH range 5.0–11.5, CAMKIV maintained both its secondary and tertiary structures, along with its function, whereas significant aggregation was observed at acidic pH (2.0–4.5). We have also performed ATPase activity assays under different pH conditions and found a significant correlation between the structure and enzymatic activities of CAMKIV. In-silico validations were further carried out by modeling the 3-dimensional structure of CAMKIV and then subjecting it to molecular dynamics (MD) simulations to understand its conformational behavior in explicit water conditions. A strong correlation between spectroscopic observations and the output of molecular dynamics simulation was observed for CAMKIV.

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