High-resolution MD Simulation Studies to Get Mechanistic Insights into the Urea-induced Denaturation of Human Sphingosine Kinase 1

Title:High-resolution MD Simulation Studies to Get Mechanistic Insights into the Urea-induced Denaturation of Human Sphingosine Kinase 1

Volume: 21 Issue: 31

Author(s): Faez Iqbal Khan, Shahid Ali, Wenjing Chen, Farah Anjum, Alaa Shafie, Md. Imtaiyaz Hassan and Dakun Lai*

Affiliation:

• School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, Sichuan,China

Keywords: Protein folding, Sphingosine kinase 1, Gibbs free energy, Protein denaturation, Protein stability, MD simulation.

Abstract:

Background: Sphingosine kinase 1 (SPhK1) is a crucial signaling enzyme involved in cell proliferation, cellular survival, stimulation of angiogenesis, and apoptosis prevention. Recently, we have reported the unfolding kinetics of SPhK1 using molecular dynamics (MD) simulation, circular dichroism, and fluorescence spectroscopy. We found that SPhK1 showed a biphasic unfolding with an intermediate state (~ 4.0 M urea).

Objective: We aim to understand the impact of MD simulation duration on the structure, function, and dynamics of proteins. In order to get deeper insights into the folding mechanism, an extended MD simulation is required.

Methods: Here, we extended the MD simulations time scale from 100 to 300 ns on SPhK1 at increasing urea concentration to explore structural changes in the SPhK1.

Results: The results suggested a constant form of the unfolding of SPhK1 upon extending the simulation time scale at different urea concentrations. Furthermore, we showed step by step unfolding and percentage of secondary structure contents in SPhK1 under the influence of urea at each concentration.

Conclusion: The results from the current work revealed a uniform pattern of the SPhK1 unfolding at different urea concentrations. This study provides deeper mechanistic insights into the urea-induced denaturation of SPhK1.

Cite this article as:

Khan Iqbal Faez , Ali Shahid , Chen Wenjing, Anjum Farah , Shafie Alaa , Hassan Imtaiyaz Md. and Lai Dakun *, High-resolution MD Simulation Studies to Get Mechanistic Insights into the Urea-induced Denaturation of Human Sphingosine Kinase 1, Current Topics in Medicinal Chemistry 2021; 21 (31) . https://dx.doi.org/10.2174/1568026621666211105095731