Showing papers by "R. Rajasekaran published in 2012"

Exploring the cause of oseltamivir resistance against mutant H274Y neuraminidase by molecular simulation approach.

Abstract: Oseltamivir (Tamiflu) is the preferred anti-viral drug employed to fight the flu virus in infected individuals. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infections. Until recently, only a low prevalence of neuraminidase inhibitors (NAIs) resistance (<1 %) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a H274Y neuraminidase mutation that was highly resistant to the NAI, oseltamivir. In this study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular docking and molecular dynamics simulation approach. Our results suggested that wild-type NA could be more indispensable for the oseltamivir binding, as characterized by minimum number of H-bonds, high flexibility and largest binding affinity than mutant-type NA. This study throws light on the possible effects of drug-resistant mutations on the large functionally important collective motions in biological systems.

Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease.

Abstract: In this work, the most detrimental missense mutations of aspartoacylase that cause Canavan’s disease were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 30 missense mutations, I-Mutant 2.0, SIFT and PolyPhen programs identified 22 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 22 variants was performed to understand the change in their conformations with respect to the native aspartoacylase by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 22 mutants were docked with the substrate NAA (N-Acetyl-Aspartic acid) to explain the substrate binding efficiencies of those detrimental missense mutations. Among the 22 mutants, the docking studies identified that 15 mutants caused lower binding affinity for NAA than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 15 mutants was caused by altered flexibility in the amino acids that bind to NAA compared with the native protein. Thus, the present study showed that the majority of the substrate-binding amino acids in those 15 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant aspartoacylases and NAA.

Development of cancer database by amalgamation of various existing database

Abstract: Cancer (medical term: malignant neoplasm) is a class of disease in which a group of cells display uncontrolled growth through division beyond normal limits, invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, in which cancer cells spread to other locations in the body via lymph or blood. These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, and do not invade or metastasize. Cell reproduction is an extremely complex process, which is normally tightly regulated by several classes of genes including oncogenes and tumor suppressor genes. Hereditary or acquired abnormalities in these regulatory genes can lead to uncontrolled cell growth, and the development of cancer. There are different of Cancer like bladder cancer, breast cancer, colon cancer, endometrial cancer, kidney cancer (renal cell), leukemia, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, thyroid cancer. To find different types of genes for different types of cancer with other related genetic information is of great importance for clinicians and cancer immunologists to detect. In the present work, a database containing various information about the different type of cancer causing gene, NCBI ID, PDB IB, SWISS PROT ID, KEGG pathway and other information has been developed with Codon bias Concept. The main emphasis in this database is introduction of Codon Usage Bias which refers to differences in the frequency of occurrence of synonymous codons in coding DNA. The advantages of this database are that it is freely available and can be used even by a layman. It is easily up gradable and quite cost effective. The most important advantage is that it would be helpful in carrying out further research in developing countries like India where cancer has a high occurrence even in poorer sections of the society.

In Silico Analysis of Detrimental Missense Mutations on SAP and Its Effect on Interactions with SLAM

Abstract: Inherited disease susceptibility in humans is most often associated with single nucleotide polymorphisms (SNPs). In this study, we computationally identified the most detrimental missense mutations in SH2 (Src homology 2) domain of SAP (signaling lymphocyte activation molecule (SLAM)-associated protein). Out of 20 variants, 14 missense mutations were commonly found to be less stable, deleterious and damaging by I-Mutant2.0, SIFT and PolyPhen programs, respectively. Subsequently, we performed modeling for these 14 variants to understand the conformational changes with respect to the native structure of SAP by computing their RMSD (root mean square deviation). The superimposed structures between native and these 14 mutants established the RMSD in the range of 0.02 A to 0.14 A. Further, the native and 14 mutants were docked with SLAMpeptide to explain the binding affinity of these detrimental missense mutations. From this analysis, we found that a total of 14 mutants, namely, H8D, G16D, G27S, L31P, R32T, D33Y, C42W, T53I, Y54C, R55L, I84T, F87S, Q99P and V102G showed less binding affinity with the SLAM-peptide in the form of Rosetta energy score. Finally, we analyzed that the loss of binding affinity of these 14 mutants of SAP, was due to altered flexibility in their binding amino acids with SLAM-peptide as compared with native type by normal mode analysis.