Biology subjects

Rathinavelan, T.

Publications and source records attributed to Rathinavelan, T..

10 recordsLinked to original sources

bioRxiv2025

Untangling or further entangling? Revelation of the complicated world of nucleic acid quadruplex folds

Quadruplexes are four-stranded nucleic acid secondary structures playing diverse biological roles. A recent meticulous analysis of known quadruplex structures formed from synthetic oligonucleotides shows that quadruplexes can take 33 distinct structural motifs (pair of stacked quartets) that act as scaffolds for simple (multi-layered quartets) and complex (multi-motifs) quadruplex folds. These motifs differ from one another in terms of interstrand connectivity and orientation. The connectivity is primarily governed by diagonal loops that connect alternate strands, and lateral and propeller loops that connect adjacent strands. These loops are absent in the tetramer, wherein interstrand orientation alone dictates the motif type. Nevertheless, a key question that remains unresolved is the complete structural landscape of quadruplex motifs, limiting our understanding of the fold-dependency in various biological functions and diseases. To address this, a total of 156 unique theoretically possible quadruplex motifs are mathematically devised here. A tool named 3D-NuS-Qplex (https://project.iith.ac.in/3d-nus-qplex/) has also been developed to model all the theoretically possible energy-minimized quadruplex folds with the options to incorporate overhangs and non-G-quartets (in addition to G-quartets) in both DNA and RNA contexts. The diversity of quadruplex motifs reported here provides new insight into their structural complexity, which appears greater than previously anticipated. HighlightsO_LIQuadruplex folds can be segmented into two-layered structural motifs that act as their scaffold C_LIO_LI156 unique theoretically possible quadruplex motifs are mathematically devised, and an option to model them is discussed C_LIO_LIThis reveals the complexity of quadruplex structures and offers new perspectives on quadruplex biology and disease C_LI

bioinformatics↗

bioRxiv2025

Modulation of Saccharomyces cerevisiae Stm1_N1-113 and human AB42 amyloid fibril morphology by 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)-1H-benzimidazolium) dibromide

Acridine derivatives are among the oldest and most effective classes of chemotherapeutic agents, exhibiting a broader spectrum of bioactivities like antitumor, antifungal, antimicrobial, and antiviral. They remain a preferred choice for molecular imaging of amyloid as well as for inhibiting amyloid fibrillation or stabilizing the fibril. This study reports the effect of a newly reported acridine compound 3,3-(acridine-4,5-diylbis(methylene)) bis(1-(carboxymethyl)-benzimidazolium) dibromide (henceforth, Ac-BIM-acid) on the amyloid-like fibrillation of N-terminal region of Saccharomyces cerevisiae Stm1 protein (Stm1_N1-113) and human A{beta}42. Modulation of Stm1_N1-113 amyloid-like structures at 400 {micro}M concentration with respect to varying concentrations of Ac-BIM-acid is revealed by AFM and NMR. While 2D-HSQC NMR spectra show the binding of Ac-BIM-acid with 400 {micro}M Stm1_N1-113, AFM captures the morphological changes of Stm1_N1-113 in response to 1 mM and 2.5 mM Ac-BIM-acid at physiological salt concentration in a time-dependent manner. Similarly, Ac-BIM-acid is shown to modulate the amyloid morphology of human A{beta}42 protein, responsible for Alzheimers disease, captured in AFM. Docking studies carried out indicate that the hydrophobic acridine ring binds at the hydrophobic pocket of the N-terminal {beta}-sheet and its neighboring {beta}-sheet of the A{beta}42 monomorphic fibril. Thus, Ac-BIM-acid would be yet another addition to the class of acridine derivatives that modulate amyloid fibrillation.

molecular biology↗

bioRxiv2024

The entangled world of DNA quadruplex folds

DNA quadruplexes take part in many biological functions. It takes up a variety of folds based on the sequence and environment. Here, a meticulous analysis of experimentally determined 392 quadruplex structures (388 PDB IDs) deposited in PDB is carried out. The analysis reveals the modular representation of the quadruplex folds. 48 unique quadruplex motifs (whose diversity arises out of the propeller, bulge, diagonal, and lateral loops that connect the quartets) are identified, leading to simple to complex inter-/intra-molecular quadruplex folds. These structural two-layered motifs are further classified into 33 continuous and 15 discontinuous motifs. The discontinuous motifs cannot further be classified into parallel, antiparallel, or hybrid as one or more guanines of the adjacent quartets are not connected. While the continuous motifs can be extended to a quadruplex fold, the discontinuous motif requires additional loop(s) to complete a fold, as illustrated here with examples. Similarly, the higher-order quadruplex folds can also be represented by continuous or discontinuous motifs or their combinations. Such a modular representation of the quadruplex folds may assist in custom engineering of quadruplexes, designing motif-based drugs, and the prediction of quadruplex structure. Further, it could facilitate understanding the role of quadruplexes in biological functions and diseases.

biochemistry↗

bioRxiv2024

NuCDB: A databank of nucleic acids circular dichroism spectra

Nucleic acids take a variety of secondary structures depending on the sequence and environmental conditions. Circular dichroism (CD) spectroscopy quickly provides the secondary structural information of nucleic acids. Nucleic acid Circular-dichroism DataBank (NuCDB) https://project.iith.ac.in/nucdb/, a repository of nucleic acid secondary structure CD spectra published during 1964-2012, is created. Besides acting as the repository for the nucleic acids CD spectra, NuCDB also has the facility to upload recently published CD spectra to keep the repository up-to-date. This repository provides the sequence-structure-environmental relationship of different nucleic acid fragments in one platform. Until today, CD is used for studying the secondary structure of smaller nucleic acid fragments. Since different parts of the genome and transcriptome of an organism have combinations of various secondary structures and play a crucial role in regulating the biological processes, the CD spectra of longer nucleic acid sequences would be more realistic. Thus, this bioinformatics repository would be helpful in training machine learning models to predict the presence of multiple secondary structures in a given CD spectra.

bioinformatics↗

bioRxiv2024

Molecular Dynamics Trajectory Analysis of Permeation (MDTAP): A tool to analyze permeation events across membrane proteins

Background and ObjectiveMolecular dynamics (MD) simulations are indispensable and versatile in capturing the time-dependent conformational changes of biomolecules to shed light on the concomitant biological processes. MD is used to provide critical mechanistic insights into the transportation of solvent/solute/drug molecules across protein channels embedded in a membrane bilayer. The huge size and volume of the MD trajectories of a membrane-embedded system provide challenges in the analyses of membrane permeation events. Thus, a software, Molecular Dynamics Trajectory Analysis of Permeation (MDTAP), is presented here to analyze the permeation events across membrane-embedded proteins and nucleic acids automatically. MethodsA software is developed here to automatically detect the permeation events across the channels irrespective of their shape and size and the type of solute molecules from the MD trajectories. MDTAP employs bash scripts to fetch information about the permeation, residence time, and diffusion of the molecules of interest in a Linux/Mac-based environment. The source code of MDTAP is freely available to the public, along with installation and usage information on GitHub (attached as supplementary for the review process and will be made accessible to the public through the following link upon acceptance for publication: https://github.com/MBL-lab/MDTAP). ResultsThe efficiency of MDTAP is demonstrated here by considering the MD trajectories of 2 water-conducting channels as test cases: E. coli outer membrane protein Wzi and E. coli Aquaporin Z. The dimensions of the channels and their capacity to accommodate and conduct water, the number of permeating water molecules along with the path traced and time taken to cross the channel is validated. ConclusionIn summary, the graphical representation of the time-dependent behavior of the solute/solvent permeation events corresponding to an MD trajectory in MDTAP allows the user to easily visualize the mechanism of permeation, including the localization of the permeating molecule (if any) and permeating path. Thus, MDTAP immensely reduces the difficult task of manually analyzing solute/solvent permeations from the bulk MD trajectories. Such a simplistic representation of permeation events across the protein transporters helps in the design of drug molecules to treat the associated diseases. Further, MDTAP is also designed to characterize the permeation events across artificial nucleic acid channels, considering their importance in recent times.

biophysics↗

bioRxiv2022

G-quadruplex landscape and its regulation revealed by a new antibody capture method

Our understanding of DNA G-quadruplexes (G4s) from in vitro studies has been complemented by genome-wide G4 landscapes from cultured cells. Conventionally, the formation of G4s is accepted to depend on G-repeats such that they form tetrads. However, genome-wide G4s characterized through high-throughput sequencing suggest that these structures form at a large number of regions with no such canonical G4-forming signatures. Many G4-binding proteins have been described with no evidence for any protein that binds to and stabilizes G4s. It remains unknown what fraction of G4s formed in human cells are protein-bound. The G4-chromatin immunoprecipitation (G4-ChIP) method hitherto employed to describe G4 landscapes preferentially reports G4s that get crosslinked to proteins in their proximity. Our current understanding of the G4 landscape is biased against representation of G4s which escape crosslinking as they are not stabilized by protein-binding and presumably transient. We report a protocol that captures G4s from the cells efficiently without any bias as well as eliminates the detection of G4s formed artifactually on crosslinked sheared chromatin post-fixation. We discover that G4s form sparingly at SINEs. An application of this method shows that depletion of a repeat-binding protein CGGBP1 enhances net G4 capture at CGGBP1-dependent CTCF-binding sites and regions of sharp interstrand G/C-skew transitions. Thus, we present an improved method for G4 landscape determination and by applying it we show that sequence property-specific constraints of the nuclear environment mitigate G4 formation.

genomics↗

bioRxiv2020

Global variation in the SARS-CoV-2 proteome reveals the mutational hotspots in the drug and vaccine candidates

To accelerate the drug and vaccine development against the severe acute respiratory syndrome virus 2 (SARS-CoV-2), a comparative analysis of SARS-CoV-2 proteome has been performed in two phases by considering manually curated 31389 whole genome sequences from 84 countries. Among the 9 mutations that occur at a high significance (T85I-NPS2, L37F-NSP6, P323L-NSP12, D614G-spike, Q57H-ORF3a, G251V-ORF3a, L84S-ORF8, R203K-nucleocapsid and G204R-nucleocapsid), R203K-nucleocapsid and G204R-nucleocapsid are co-occurring (dependent) mutations and P323L-NSP12 and D614G-spike often appear simultaneously. Other notable variations that appear with a moderate to low significance are, M85-NSP1 deletion, D268-NSP2 deletion, 112 amino acids deletion in ORF8, a phenylalanine insertion amidst F34-F36 (NSP6) and several co-existing (dependent) substitution/deletion (I559V & P585S in NSP2, P504L & Y541C in NSP13, G82 & H83 deletions in NSP1 and K141, S142 & F143 deletions in NSP2) mutations. P323L-NSP12, D614G-spike, L37F-NSP6, L84S-ORF8 and the sequences deficient of the high significant mutations have led to 4 major SARS-CoV-2 clades. The top 5 countries bearing all the high significant and majority of the moderate significant mutations are: USA, England, Wales, Australia and Scotland. Further, the majority of the significant mutations have evolved in the first phase and have already transmitted around the globe indicating the positive selection pressure. Among the 26 SARS-CoV-2 proteins, nucleocapsid protein, ORF3a, ORF8, RNA dependent RNA polymerase and spike exhibit a higher heterogeneity compared with the rest of the proteins. However, NSP9, NSP10, NSP8, the envelope protein and NSP4 are highly resistant to mutations and can be exploited for drug/vaccine development.

bioinformatics↗

bioRxiv2020

K-PAM: A unified platform to distinguish Klebsiella species K- and O-antigen types, model antigen structures and identify hypervirulent strains

A computational method has been developed to distinguish the Klebsiella species serotypes to aid in outbreak surveillance. A reliability score (estimated based on the accuracy of a specific K-type prediction against the dataset of 141 distinct K-types) average(ARS) that reflects the specificity between the Klebsiella species capsular polysaccharide biosynthesis and surface expression proteins, and their K-types has been established. ARS indicates the following order of potency in accurate serotyping: Wzx(ARS=98.5%),Wzy(ARS=97.5%),WbaP(ARS=97.2%),Wzc(ARS=96.4%),Wzb(ARS=9 4.3%),WcaJ(ARS=93.8%),Wza(ARS=79.9%) and Wzi(ARS=37.1%). Thus, Wzx, Wzy and WbaP can give more reliable K-typing compared with other proteins. A fragment-based approach has further increased the Wzi ARS from 37.1% to 80.8%. The efficacy of these 8 proteins in accurate K-typing has been confirmed by a rigorous testing and the method has been automated as K-PAM(www.iith.ac.in/K-PAM/). Testing also indicates that the use of multiple genes/proteins helps in reducing the K-type multiplicity, distinguishing the K-types that have identical K-locus(like KN3 and K35) and identifying the ancestral serotypes of Klebsiella spp. K-PAM has the facilities to O-type using Wzm(ARS=85.7%) and Wzt(ARS=85.7%) and identifies the hypervirulent Klebsiella species by the use of rmpA,rmpA2,iucABCD,iroBCDN and iutA marker genes. Yet another highlight of the server is the repository of the modeled 11 O- and 79 K - antigen 3D structures.

bioinformatics↗

bioRxiv2020

Secondary structural characterization of the nucleic acids from circular dichroism spectra using extreme gradient boosting decision-tree algorithm

Nucleic acids exhibit a repertoire of conformational preference depending on the sequence and environment. Circular dichroism (CD) is an important and valuable tool for monitoring such secondary structural conformations of nucleic acids. Nonetheless, the CD spectral diversity associated with these structures poses a challenge in obtaining the quantitative information about the secondary structural content of a given CD spectrum. To this end, the competence of extreme gradient boosting decision-tree algorithm has been exploited here to predict the diverse secondary structures of nucleic acids. A curated library of 610 CD spectra corresponding to 16 different secondary structures of nucleic acids has been developed and used as a training dataset. For a test dataset of 242 CD spectra, the algorithm exhibited the prediction accuracy of 99%. For the sake of accessibility, the entire process is automated and implemented as a webserver, called CD-NuSS (CD to nucleic acids secondary structure) and is freely accessible at https://www.iith.ac.in/cdnuss/. The XGBoost algorithm presented here may also be extended to identify the hybrid nucleic acid topologies in future.

bioinformatics↗

bioRxiv2020

STRIDER: Steric hindrance estimator

In silico modeling plays a vital role in the de novo designing and docking of biomacromolecules as well as in exploring their conformational dynamics. Additionally, it has a major role in acquiring the structural insights from the parameters derived from the experimental techniques such as cryo-electron microscopy. Steric hindrance is one of the important measures to validate the accuracy of the constructed model. A web user interface (WUI) namely, STRIDER (steric hindrance estimator) (www.iith.ac.in/strider/) can estimate and report pairwise inter- and intra- molecular steric hindrances using the van der Waals radius of 117 elements through a user interactive interface. STRIDER also identifies and reports the coordination number of 64 metals along with their interacting pattern in an interactive mode. STRIDER can analyze an ensemble of conformers, wherein, multiple conformers are used to circumvent sampling issue in flexible docking, understand protein folding and facilitate structure based virtual screening. Further, it generates a pymol session file that can be used for offline analysis. As STRIDER simply requires the Cartesian coordinates of the given molecule in protein data bank format, any chemical structure can be an input. AvailabilityIt can be freely accessible through: www.iith.ac.in/strider/ without any registration. Theme Of the Concept O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/931550v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@7be933org.highwire.dtl.DTLVardef@10b2e30org.highwire.dtl.DTLVardef@1056b7eorg.highwire.dtl.DTLVardef@d42f28_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗