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 Anaplastic lymphoma kinase (ALK) is an important target in the treatment of cancer, especially non-small cell lung cancer (NSCLC) with gene rearrangements. In this study, the effects of three tyrosine kinase inhibitors (TKIs) including Crizotinib, Ceritinib, and Alectinib on the ALK tyrosine kinase domain were investigated and compared using molecular dynamics (MD) simulations. Various analyses such as RMSD, radius of gyration (RG), solvent accessible surface area (SASA), hydrogen bond number (Hbond), principal component analysis (PCA), and MMPBSA were used in this study.
Molecular dynamics simulations for 100 ns showed that Alectinib resulted in structural stability, reduced solvent accessible surface area (SASA) compared to Crizotinib and Ceritinib, and greater protein compaction. MMPBSA results also indicated a lower binding free energy and higher binding affinity of Alectinib to ALK, which enhances its efficacy. The use of Alectinib, due to its high ability to cross the blood-brain barrier and its effect on brain metastases, can improve treatment efficacy and reduce drug resistance. These results and findings indicate that Alectinib can be an option for first-line treatment.

Abstract PFU DNA polymerse shows the lowest error rate in Polymerase Chain Reaction (PCR) but it seperates from DNA after about 20 nucleotides add to the end of primer strand. The research purpus is processivity improvement of PFU DNA polymerase by means of rational design and point mutation due to lowest enthropy and enthalpy costs. so DNA polymerases in B family with high processivity were selected and their structures and sequences were compared with PFU DNA polymerase then an optimized mutation was induced . Native form and mutant were simulated for 100 ns and the trajectories were analyzed. ΔG_binding was calculated by g_mmpbsa tool and proved that the mutant shows a robust affinity .

Abstract The COVID-19 pandemic has created a global health crisis, and developing effective treatments is essential to prevent the spread of the disease and save millions of lives. One of the key proteins involved in the replication cycle of SARS-CoV-2, the virus that causes COVID-19, is the main protease enzyme, 3CL^pro. Due to its high importance, this enzyme is the subject of molecular, structural, and clinical investigations, and efforts have been made to develop drugs that can inhibit its activity. One such drug is the chemical compound N3, which has been found to have a high inhibitory effect against 3CL^pro. However, traditional medicine perspectives on this issue have been less explored. In this research, molecular docking interaction simulation and all-atom molecular dynamics (MD) simulation were conducted to study the potential inhibitory capability of generally available 21 plant-extracted compounds against the 3CL^pro enzyme. Three compounds with the highest inhibition probability were selected from the molecular docking results and subjected to 100 ns of MD simulation to investigate their stability and structural-dynamic-energetic features. Beside the complexes stability, the results from the simulation demonstrated that, all our selected three compounds induce N3 comparable structural-dynamics characteristics to 3CL^pro and, therefore, are expected to have a similar inhibitory ability against this enzyme. Compound number 5 was found to have the most favorable binding energy and was proposed as the best plant substitute for N3. The results from this research can be directly used to design experimental research for 3CLpro enzyme inhibition, saving the time-financial cost.

Abstract is one of the bacterial outer membrane protein which can transfer the ions into the membrane. During the last years different theoretical and experimental methods have been used for the investigation of the bacterial protein. In this study for retaining periodic boundary condition and investigation of the channel structural changes, we use double lipid bilayer in the system. Different ion concentration was applied into the lipid bilayers to make simulation much more realistic. The aim of this simulation is if there is any prominent direction in the ion passage of the channels. Structural analysis for two proteins with a different orientation is dissimilar and dssp analysis shows different peaks although there are common peaks. Lining residues and constriction zone amino acids in the two final frames are also diverse. There is no ion passage thorough protein 2. The results are completely different for the ion channels and it shows which after 100ns simulation one of the channels which its direction is similar to the natural channel in the bacterial membrane is open and the ion passage is clear and the other channel is completely closed which is related to the direction of the channel due to the ion concentration.

Abstract Aims: Information of the protein structure is essential to understand the protein functions. Flexibility is one of the most important characteristics related to protein functions. Knowledge about flexibility of the protein structures can be helpful to improve protein structure prediction and comprehend their function. This study was conducted with the aim of investigating the flexibility prediction of protein structures, using support vector machine.
Materials and Methods: In this study, a balanced dataset containing 95 proteins was used. The features used in the present study for modeling amino acids formed a 33-dimensional vector. Some of them were obtained by crawling a window with the length of 17 focusing on the target amino acid on the protein chain, and some were only related to the target amino acid. To define the flexibility factor, the characteristics based on the information derived from the two-dimensional angular variations was used. The information was calculated for each amino acid by considering the position of each amino acid alone and for the adjacent amino acid pairs in a seventeenth window, and the support vector machine method was used for prediction.
Findings: The accuracy was 73.1%, F-measure was 71%, precision was 73%, and sensitivity was 73.2%. Acceptable superiority of the proposed method was confirmed in comparison with the current methods. The angular representation of each protein was able to accurately demonstrate the 3D characteristics and properties of the protein structure.
Conclusion: The accuracy is 73.1%, F-measure is 71%, precision is 73%, and sensitivity is 73.2% and angular aspect is the best descriptor for flexibility prediction. Angular representation of each protein can accurately reflect the 3D characteristics and properties of the protein structure.