Modares Journal of Biotechnology

Abstract Epidermal growth factor receptor (EGFR) is one of the most important tyrosine kinase receptors that plays a key role in regulating cellular processes and the progression of many cancers, including lung cancer. In this study, the effects of second-generation EGFR inhibitors, including Afatinib, Dacomitinib, and Neratinib, as well as the candidate drugs Canertinib and Poziotinib, on wild-type EGFR were investigated using molecular dynamics (MD) simulations. For this purpose, structural data were collected and analyzed from reliable databases. Molecular docking studies led to the identification of drug binding sites, and molecular dynamics (MD) simulations under physiological conditions investigated stability and ligand-protein interactions. The parameters such as RMSD, radius of gyration (Rg), SASA, and hydrogen bonds were calculated to evaluate the stability of the protein-ligand complex. The results of the MMPBSA analysis showed that Neratinib, with the lowest free energy of binding (ΔG), has a higher binding affinity to EGFR and demonstrated greater stability during the simulation. Also, the principal component analysis (PCA) showed that the EGFR-Neratinib complex has less dynamics and occupies less phase space, which indicates more stability of this complex.
These results show that of all the compounds studied, Neratinib may be the most potent and promising candidate in advancing combination therapies against EGFR.

Abstract Matrix metalloproteinases (MMPs) are a zinc endopeptidase family that increases the metastatic behavior of human malignant tumors. Epigallocatechin gallate (EGCG) is a major component of green tea polyphenols and is used as an MMP inhibitor in cancer treatment. This study aims to develop and optimize the loading of EGCG in the liposomal delivery system in an experimental/ computational way. In this study, nanoliposomes were prepared by passive loading and thin-film hydration method. Size, zeta potential, stability, encapsulation efficiency, and nanoliposome drug release profile were investigated. Cytotoxicity of nanoliposomes was evaluated on three breast cancer cell lines using an MTT viability assay. To investigate the EGCG-Liposome interaction, coarse-grained Molecular Dynamic simulations were carried out. The mean diameter of liposome was 73.6±6.9 nm, the surface charge was -14.6 mV and the encapsulation efficiency was 78.5±7.3%. The encapsulation of EGCG into the liposome caused a continuous release of the drug after 72 h, which also increased the potency of the drug. Due to the EGCG hydrophobic properties, the major distribution is located at the hydrophobic part of the membrane. The energy and radial distribution function results indicate the stability of liposomes. Simulation results demonstrate that the majority of the drug is surrounded by liposomes, which indicates high encapsulation efficiency and confirms the developed synthesis method. Due to the low solubility of the drug, it seems that the use of liposomal carriers to deliver and release EGCG is a suitable solution to increase the efficiency of the drug.

Abstract Glucoamylase, is an important economic enzyme due to its ability to hydrolyze starch and β-D-glucose polymers. Understanding of factors affecting the thermal stability of the glucoamylase enzyme is critical in the production of isoenzymes with high heat or cold stability. In this study, the effect of temperature on the structure and properties of each of the isoenzymes of the mesophilic, thermophilic and psychrophilic glucoamylase were studied. For this purpose, molecular dynamics simulation was used to assess these factors and structural differences. 240 nanosecond of MD simulation was done for three isoenzymes of glucoamylase in four temperatures at 300, 350, 400 and 450 K. The variations of each of these parameters were compared for three isoenzymes, and it was found that among the computable factors in molecular dynamics simulation, electrostatic energy of protein with water, van der Waals energy between proteins and water, free energy solubility (∆G_solvation), instability parameter, nonpolar solvent accessible surface, and total solvent accessible surface can be used to predict thermal stability of a protein during increase of temperature.

Abstract Liposomes or biological vesicles are formed from cholesterol, phospholipids, and water. Also, sometimes other biological and non-biological molecules imported in the structure of liposome. The stability of the liposomes in the treatment of diseases and drug delivery, it is vitally important and can be influenced by the composition of phospholipid. In addition, the presence or absence of cholesterol may also affect the stability of liposome. Also, the formation of liposomes is affected by the presence or absence of cholesterol. In this study, we are seeking to affect the presence or absence of cholesterol on the stability and the formation of the liposome. For this purpose, the molecular dynamics simulation method is used. Liposomes that they are simulated was of two types of liposomes type I and liposome type II. The formation analyzes including radial distribution function and solvent accessible surface area showed that each of liposomes created. The type I liposome created one nanodisc structure and type II liposome created two nanodisc structures. Also, energy analysis including total energy, van der Waals interaction energy, and electrostatic interaction energy showed that type I liposome is more stable. Because the cholesterol molecules are the presence of in this liposome structure, that ability to gives hydrogen bonding with side lipids and an increase of stability. In addition, hydrophobic interactions between cholesterol and phospholipids as well as distribution and proper orientation of these parts play a major stake in the stability of the structure.

Abstract Aims: Targeting DNA lies at the heart of anti-cancer therapies. Hence, DNA-binding drugs and their interaction with DNA have recently drawn the attention of researchers. Since DNA minor groove binders (MGBs) act as potent anti-tumor agents, there is a need to have detailed insights on how they interact with DNA. The mechanism of action of the majority of MGBs is not well studied at the molecular level.
Materials and Methods: Herein, molecular docking and dynamics simulations were performed, using AutoDock Vina and NAMD softwares, respectively, to evaluate the binding of A derivatives (Tallimustine, PNU 151807, and ) to , and to compare their interaction energy and binding patterns.
Findings: All three drugs were stably bound throughout the simulation, causing only minor modifications to the structure of DNA. Results of interaction energy analyses together with LigPlot outcomes showed that A/T residues are responsible for making the majority of non-bonding interactions in the case of all three drugs, showing a good agreement with previously reported findings on MGBs.
Conclusion: A/T residues are responsible for making the majority of non-bonding interactions in the case of all three drugs, showing a good agreement with previously reported findings on MGBs. Furthermore, our studies have shown that to the other members of the Distamycin A family, makes stronger interactions with , making it a better candidate for cancer therapy goals.

Abstract Aims: Molecular insights into the analyte-bioreceptor interactions play a vital role in the efficacy of designing biosensors. Biosensors that utilize aptamers as bioreceptors are highly efficient with high specificity and reusability. Aptasensors can be used in a variety of conditions of in vivo or in vitro. The aim of this study was to study the changes in the solvent conditions of the binding of MUC1-G peptide and the anti-MUC1 aptamer.
Materials and Methods: The molecular dynamics simulation method has been used to investigate the change of molecular interactions due to selective variations in solvent conditions. The results can be used to reflect a variety of environments, in which the aptasensor utilizes anti-MUC1 S2.2 aptamer as a bioreceptor and MUC1–G peptide as a biomarker.
Findings: Based on the calculated binding energies, the medium containing 0.10M NaCl and anti-MUC1 S2.2 aptamer demonstrates the highest affinity toward the MUC1-G peptide among the studied concentrations of NaCl, and the arginine amino acid has a key role in the aptamer–peptide binding. Conclusion: The results of MD simulation indicated that the increase in the concentration of NaCl in the interaction environment leads to a decrease in binding energies; therefore, the binding affinity of the anti-MUC1 aptamer to MUC1-G peptide decreases. Insights from present modeling demonstrate the selectiveness and sensitivity to solvent conditions, which should be considered in the development of biosensors.

Abstract Bacteriorhodopsin (bR) is a membrane protein that acts as a light-driven proton pump in Halobacterium salinarum. This protein contains seven transmembrane α-helical subunits, helices A–G, one beta-sheet and a retinal chromophore. Studies show that bR have the property of absorbing the microwave. Among several methods molecular dynamics simulation (MD) is the most systemic approach. With this method we can study structural changes and dynamic of macromolecules. In this project, we use modeling and molecular dynamic simulation. To obtain more accurate structures after the equilibration a 15 ns MD simulation was done. After that, in order to find the effective sites of microwave absorption on bR a production run was performed with applying electric field in the time intervals of 786 ps that is equal to one sinusoidal frequency at microwave spectrum. At last, conformational changes under effect of sinusoidal wave has been assigned the effective sites of microwave absorption in the protein. Our study shows that microwave in the frequency of 8 GHZ and the time interval that mentioned above, cannot make significant changes on the protein. In the other hand, we have seen some reversible changes in Beta-sheet and D, C, B helices.