C. Sudandiradoss

Bio: C. Sudandiradoss is an academic researcher from VIT University. The author has contributed to research in topics: Docking (molecular) & Single-nucleotide polymorphism. The author has an hindex of 13, co-authored 39 publications receiving 559 citations.

Exploring the structural constraints at cleavage site of mucin 1 isoform through molecular dynamics simulation

Abstract: In silico alanine scanning mutagenesis on the cleavable isoform of mucin 1 revealed isoleucine 67 as one of the key factors contributing to the strain at the autoproteolytic cleavage site. In this study, we demonstrate the structural basis of isoleucine-induced rigidity towards the strain-driven autoproteolysis at G−1S+1 cleavage site of mucin 1. We further evaluated the gain in flexibility upon isoleucine 67 mutation through molecular dynamics and essential dynamics studies. The results show that the mutant exhibits stability in its secondary structural elements while the native displays a less-bonded network, however the cleavage site of native remains constrained. Essential dynamics revealed that large motions of the mutant were confined to the loop although the internal domain of the structure remains unaffected. Also, the mutation exerted a larger effect on the intraprotein interactions and consequently resulted in a stabilized motif at the cleavage. Analyses on MD trajectory conformations illustrate a completely disrupted motif in native as an effect of the peptide strain. The study also revealed that in mutant, the cleavage competent catalytic groups C=O and OG were in geometrical aspects unfavorable for a nucleophilic attack. The results support the earlier speculation that the presence of bulky isoleucine proximal G−1S+1 cleavage site limits the conformational sampling of residues and therefore maintains the residues in a torsionally restrained conformation.

In silico investigations on functional and haplotype tag SNPs associated with congenital long QT syndromes (LQTSs)

Abstract: Single-nucleotide polymorphisms (SNPs) play a major role in the understanding of the genetic basis of many complex human diseases. It is still a major challenge to identify the functional SNPs in disease-related genes. In this review, the genetic variation that can alter the expression and the function of the genes, namely KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2, with the potential role for the development of congenital long QT syndrome (LQTS) was analyzed. Of the total of 3,309 SNPs in all five genes, 27 non-synonymous SNPs (nsSNPs) in the coding region and 44 SNPs in the 5′ and 3′ un-translated regions (UTR) were identified as functionally significant. SIFT and PolyPhen programs were used to analyze the nsSNPs and FastSNP; UTR scan programs were used to compute SNPs in the 5′ and 3′ untranslated regions. Of the five selected genes, KCNQ1 has the highest number of 26 haplotype blocks and 6 tag SNPs with a complete linkage disequilibrium value. The gene SCN5A has ten haplotype blocks and four tag SNPs. Both KCNE1 and KCNE2 genes have only one haplotype block and four tag SNPs. Four haplotype blocks and two tag SNPs were obtained for KCNH2 gene. Also, this review reports the copy number variations (CNVs), expressed sequence tags (ESTs) and genome survey sequences (GSS) of the selected genes. These computational methods are in good agreement with experimental works reported earlier concerning LQTS.

Casting the critical regions in nucleotide binding oligomerization domain 2 protein: a signature mediated structural dynamics approach.

Abstract: Nucleotide binding oligomerization domain 2 (NOD2), a protein involved in the first line defence mechanism has a pivotal role in innate immunity Impaired function of this protein is implicated in disorders such as Blau syndrome and Crohn’s disease Since an altered function is linked to protein’s structure, we framed a systematic strategy to interpret the structure–function relationship of the protein Initiated with mutation-based pattern prediction and identified a distant ortholog (DO) of NOD2 from which the intra-residue interaction network was elucidated The network was used to identify hotspots that serve as critical points to maintain the stable architecture of the protein Structural comparison of NOD2 domains with a DO revealed the minimal number of intra-protein interactions required by the protein to maintain the structural fold In addition, the conventional molecular dynamics simulation emphasized the conformational transitions at hot spot residues between native NOD2 domains and its respec

In silico analysis of metal coordination geometry in arsenic, beryllium, and lead bound structures

Abstract: Metal toxicity is a potential hazard to health and toxic effects of metals have been implicated in many diseases. Understanding the interaction of toxic metals becomes vital to prevent hazards following its association in living systems. Coordination chemistry helps in predicting the metal environments like coordinating residues, coordination space, metal coordination geometry, etc. Our work aimed at predicting the coordination of toxic metals arsenic, lead, and beryllium. In this work, we analyzed coordination for each metal from a set of arsenic, beryllium and lead bound structures which were retrieved from the Protein Data Bank. The structures were validated using B-factor and occupancy of the coordinating residues towards the metals. Coordination patterns such as chelate residues, chelate length, geometry, coordination number and structural architecture were predicted. Coordination geometry of the metals was exposed beyond the coordination space with their coordination number ranging from 2 to 11. Ana...

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.

Using SIFT and PolyPhen to Predict Loss-of-Function and Gain-of-Function Mutations

Abstract: Context: The interpretation of novel missense variants is a challenge with increasing numbers of such variants being identified and a responsibility to report the findings in the context of all available scientific evidence. Various in silico bioinformatic tools have been developed that predict the likely pathogenicity of missense variants; however, their utility within the diagnostic setting requires further investigation. Aim: The aim of our study was to test the predictive value of two of these tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), in a set of 141 missense variants (131 pathogenic, 8 benign) identified in the ABCC8, GCK, and KCNJ11 genes. Methods: Sixty-six of the mutations caused a gain of protein function, while 67 were loss-of-function mutations. The evolutionary conservation at each residue was also investigated using multiple sequence alignments from the UCSC genome browser. Results: The sensitivity of SIFT and PolyPhen was reasonably high (69% and...

In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A/C protein

Abstract: Lamin A/C proteins are the major components of a thin proteinaceous filamentous meshwork, the lamina, that underlies the inner nuclear membrane. A few specific mutations in the lamin A/C gene cause a disease with remarkably different clinical features: FPLD, or familial partial lipodystrophy (Dunnigan-type), which mainly affects adipose tissue. Lamin A/C mutant R482W is the key variant that causes FPLD. Biomolecular interaction and molecular dynamics (MD) simulation analysis were performed to understand dynamic behavior of native and mutant structures at atomic level. Mutant lamin A/C (R482W) showed more interaction with its biological partners due to its expansion of interaction surface and flexible nature of binding residues than native lamin A/C. MD simulation clearly indicates that the flexibility of interacting residues of mutant are mainly due to less involvement in formation of inter and intramolecular hydrogen bonds. Our analysis of native and Mutant lamin A/C clearly shows that the structural and functional consequences of the mutation R482W causes FPLD. Because of the pivotal role of lamin A/C in maintaining dynamics of nuclear function, these differences likely contribute to or represent novel mechanisms in laminopathy development.

Drug resistance mechanism of PncA in Mycobacterium tuberculosis

Abstract: Tuberculosis continues to be a global health threat. Pyrazinamide (PZA) is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to PZA represents an important public health problem, as both first- and second-line treatment regimens include PZA. It becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by the bacterial pyrazinamidase (PncA) enzyme. Resistance to PZA is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are involved in resistance towards PZA. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three-dimensional (3D) conformational behaviour of native and mutants PncA. Our analy...