R. Rajasekaran

Bio: R. Rajasekaran is an academic researcher from VIT University. The author has contributed to research in topics: Mutant & Single-nucleotide polymorphism. The author has an hindex of 15, co-authored 69 publications receiving 758 citations. Previous affiliations of R. Rajasekaran include Department of Biotechnology.

In silico analysis of detrimental mutations in ADD domain of chromatin remodeling protein ATRX that cause ATR-X syndrome: X-linked disorder

Abstract: Many biological functions involve specific interactions of proteins. Mutations in ATRX gene can change the sequence and structure of a protein thereby impairing its function. Thus, the dysfunction of chromatin remodeling protein ATRX as a result of amino acid substitution in ADD domain often underlies the human disease, ATR-X syndrome. In general, it is mainly caused by amino acid substitution that interfered with the interactions of interest at the interface level. Hence, the study of protein–protein interactions and the interface that mediate the interactions stand important for understanding of biological function. In this work, we address the loss of function in chromatin remodeling protein ATRX due to loss of structural stability that affect the functional activity in mutant ADD domain by 17 missense mutations viz., G175E, N179S, P190A, P190L, P190S, L192F, V194I, C200S, Q219P, C220R, C220Y, W222S, C243F, R246C, R246L, G249C, and G249D. Furthermore, the loss of binding affinity of ADD domain with their interacting partner namely histone H3-peptide were investigated by (1) computing the RMSD (root mean square deviation) for the ADD domain of native with all the 17 mutants, (2) computing intra-molecular interactions in ADD domain of native with all the mutants, (3) computing binding affinity of native and mutant structures of ADD domain with histone H3-peptide through docking studies, and (4) cross validating the loss of function on binding affinity through inter-molecular interactions and normal mode analysis. Finally, as from our computational result, we concluded that all the parameters mentioned above used for studying ADD domain of mutant structures showed the decreased potential values compared to native structure that underlie ATR-X syndrome.

Exploring the structural and functional effect of pRB by significant nsSNP in the coding region of RB1 gene causing retinoblastoma

Abstract: In this study, we identified the most deleterious nsSNP in RB1 gene through structural and functional properties of its protein (pRB) and investigated its binding affinity with E2F-2. Out of 956 SNPs, we investigated 12 nsSNPs in coding region in which three of them (SNPids rs3092895, rs3092903 and rs3092905) are commonly found to be damaged by I-Mutant 2.0, SIFT and PolyPhen programs. With this effort, we modeled the mutant pRB proteins based on these deleterious nsSNPs. From a comparison of total energy, stabilizing residues and RMSD of these three mutant proteins with native pRB protein, we identified that the major mutation is from Glutamic acid to Glycine at the residue position of 746 of pRB. Further, we compared the binding efficiency of both native and mutant pRB (E746G) with E2F-2. We found that mutant pRB has less binding affinity with E2F-2 as compared to native type. This is due to sixteen hydrogen bonding and two salt bridges that exist between native type and E2F-2, whereas mutant type makes only thirteen hydrogen bonds and one salt bridge with E2F-2. Based on our investigation, we propose that the SNP with an id rs3092905 could be the most deleterious nsSNP in RB1 gene causing retinoblastoma.

Predicting Therapeutic Template by Evaluating the Structural Stability of Anti-Cancer Peptides—A Computational Approach

Abstract: Clinically significant antibiotic resistance has evolved against virtually every antibiotic deployed. Yet the development of new classes of antibiotics has lagged far behind our growing need for such drugs. Antimicrobial peptides (AMPs) have emerged as novel therapeutics hailed for their bactericidal and immunomodulatory properties. However, the process of optimizing antimicrobial peptide stability, using large peptide libraries is both tedious and expensive. The intent of this study is to analyze computationally the stability of anti-cancer peptides (ACPs) and to discover a potential template from a pool of ACPs for therapeutic use. Consequently we highlighted that ACP, NK-Lysin appears advantageous over the other ACPs with respect to stability, and may provide a convenient platform for the development of anticancer therapeutic peptide.

Probing the competitive inhibitor efficacy of frog-skin alpha helical AMPs identified against ACE2 binding to SARS-CoV-2 S1 spike protein as therapeutic scaffold to prevent COVID-19

Abstract: In COVID-19 infection, the SARS-CoV-2 spike protein S1 interacts to the ACE2 receptor of human host, instigating the viral infection. To examine the competitive inhibitor efficacy of broad spectrum alpha helical AMPs extracted from frog skin, a comparative study of intermolecular interactions between viral S1 and AMPs was performed relative to S1-ACE2p interactions. The ACE2 binding region with S1 was extracted as ACE2p from the complex for ease of computation. Surprisingly, the Spike-Dermaseptin-S9 complex had more intermolecular interactions than the other peptide complexes and importantly, the S1-ACE2p complex. We observed how atomic displacements in docked complexes impacted structural integrity of a receptor-binding domain in S1 through conformational sampling analysis. Notably, this geometry-based sampling approach confers the robust interactions that endure in S1-Dermaseptin-S9 complex, demonstrating its conformational transition. Additionally, QM calculations revealed that the global hardness to resist chemical perturbations was found more in Dermaseptin-S9 compared to ACE2p. Moreover, the conventional MD through PCA and the torsional angle analyses indicated that Dermaseptin-S9 altered the conformations of S1 considerably. Our analysis further revealed the high structural stability of S1-Dermaseptin-S9 complex and particularly, the trajectory analysis of the secondary structural elements established the alpha helical conformations to be retained in S1-Dermaseptin-S9 complex, as substantiated by SMD results. In conclusion, the functional dynamics proved to be significant for viral Spike S1 and Dermaseptin-S9 peptide when compared to ACE2p complex. Hence, Dermaseptin-S9 peptide inhibitor could be a strong candidate for therapeutic scaffold to prevent infection of SARS-CoV-2.

Methods in Enzymology.

Abstract: I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

Patterns of Somatic Mutation in Human Cancer Genomes

Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore PL02-05 All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Amyloid oligomers: A joint experimental/computational perspective on Alzheimer's disease, Parkinson's disease, type II diabetes, and amyotrophic lateral sclerosis

Abstract: Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.