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Deoxyribonucleic acid (DNA) is a vital biomacromolecule. Although the right-handed B-DNA type helical structure is the most abundant and extensively studied form of DNA, several noncanonical forms, such as triplex, quadruplex, Z-DNA, A-DNA, and ss-DNA, have been probed from time to time to gain insights into the DNA's function. Z-DNA was recently found to be involved in cancer and several autoimmune diseases. In the present Article, we evaluated the conformational stability of locked-sugar-based Z-DNA via all-atom explicit-solvent molecular dynamics simulations and found that the modified DNA maintained the left-handed conformation even in the absence of counterions, wherein the structural rigidity dominates over the electrostatic repulsion between the complementary strands. The control Z-DNA without counterions, as expected, instantaneously resulted in unfolded states. The remarkable stability of the conformationally locked model system was thoroughly investigated via structural and energetic perspectives and was probably the result of the backbone widening in tandem with enhanced electrostatics between complementary strands. We believe that the design of the proposed modified Z-DNA construct could help understand the otherwise delicate Z-DNA conformation even in salt-deprived conditions. The design could also motivate the medicinal use of short segments of such modified nucleotides and could be utilized in more advanced modeling techniques, such as DNA origami which has gained popularity in recent years.

DNA-protein interactions occur at all levels of DNA expression and replication and are crucial determinants for the survival of a cell. Several modified nucleotides have been utilized to manipulate these interactions and have implications in drug discovery. In the present article, we evaluated the binding of bicyclo-nucleotides (generated by forming a methylene bridge between C1' and C5' in sugar, leading to a bicyclo system with C2' axis of symmetry at the nucleotide level) to proteins. We utilized four ssDNA-protein complexes with experimentally known binding free energies and investigated the binding of modified nucleotides to proteins via all-atom explicit solvent molecular dynamics (MD) simulations (200 ns), and compared the binding with control ssDNA-protein systems. The modified ssDNA displayed enhanced binding to proteins as compared to the control ssDNA, as seen by means of MD simulations followed by MM-PBSA calculations. Further, the Delphi-based electrostatic estimation revealed that the high binding of modified ssDNA to protein might be related to the enhanced electrostatic complementarity displayed by the modified ssDNA molecules in all the four systems considered for the study. The improved binding achieved with modified nucleotides can be utilized to design and develop anticancer/antisense molecules capable of targeting proteins or ssRNAs.Communicated by Ramaswamy H. Sarma.

Antimicrobial peptides (AMPs) are major components of the innate immune defense. Accumulating evidence suggests that the antibacterial activity of many AMPs is dependent on the formation of amyloid-like fibrils. To identify novel fibril forming AMPs, we generated a spleen-derived peptide library and screened it for the presence of amyloidogenic peptides. This approach led to the identification of a C-terminal 32-mer fragment of alpha-hemoglobin, termed HBA(111-142). The non-fibrillar peptide has membranolytic activity against various bacterial species, while the HBA(111-142) fibrils aggregated bacteria to promote their phagocytotic clearance. Further, HBA(111-142) fibrils selectively inhibited measles and herpes viruses (HSV-1, HSV-2, HCMV), but not SARS-CoV-2, ZIKV and IAV. HBA(111-142) is released from its precursor by ubiquitous aspartic proteases under acidic conditions characteristic at sites of infection and inflammation. Thus, HBA(111-142) is an amyloidogenic AMP that may specifically be generated from a highly abundant precursor during bacterial or viral infection and may play an important role in innate antimicrobial immune responses. ispartof: CELLULAR AND MOLECULAR LIFE SCIENCES vol:80 issue:6 ispartof: location:Switzerland status: published

Acinetobacter baumannii is an extremely dangerous multidrug-resistant (MDR) gram-negative pathogen which poses a serious life-threatening risk in immunocompromised patients. Phosphopantothenoyl cysteine synthetase (PPCS) catalyzes the formation of an amide bond between L-cysteine and phosphopantothenic acid (PPA) to form 4′- Phosphopantothenoylcysteine during Coenzyme A (CoA) biosynthesis. CoA is a crucial cofactor for cellular survival and inhibiting its synthesis will result in cell death. Bacterial PPCS differs from eukaryotic PPCS in a number of ways like it exists as a C-terminal domain of a PPCDC/PPCS fusion protein whereas eukaryotic PPCS exists as an independent protein. This difference makes it an attractive drug target. For which a conventional iterative approach of SBDD (structure-based drug design) was used, which began with three-dimensional structure prediction of AbPPCS using PHYRE 2.0. A database of FDA-approved compounds (Drug Bank) was then screened against the target of interest by means of docking score and glide energy, leading to the identification of 6 prominent drug candidates. The shortlisted 6 molecules were further subjected to all-atom MD simulation studies in explicit-solvent conditions (using AMBER force field). The MD simulation studies revealed that the ligands DB65103, DB449108 and DB443210, maintained several H-bonds with intense van der Waals contacts at the active site of the protein with high binding free energies: −11.42 kcal/mol, −10.49 kcal/mol and −10.98 kcal/mol, respectively, calculated via MM-PBSA method. Overall, binding of these compounds at the active site was found to be the most stable and robust highlighting the potential of these compounds to serve as antibacterials. Communicated by Ramaswamy H. Sarma

The COVID-19 pandemic infection has claimed many lives and added to the social, economic, and psychological distress. The contagious disease has quickly spread to almost 218 countries and territories following the regional outbreak in China. As the number of infected populations increases exponentially, there is a pressing demand for anti-COVID drugs and vaccines. Virtual screening provides possible leads while extensively cutting down the time and resources required for ab-initio drug design. We report structure-based virtual screening of a hundred plus library of quinoline drugs with established antiviral, antimalarial, antibiotic or kinase inhibitor activity. In this study, targets having a role in viral entry, viral assembly, and viral replication have been selected. The targets include: 1) RBD of receptor-binding domain spike protein S 2) Mpro Chymotrypsin main protease 3) Ppro Papain protease 4) RNA binding domain of Nucleocapsid Protein, and 5) RNA Dependent RNA polymerase from SARS-COV-2. An in-depth analysis of the interactions and G-score compared to the controls like hydroxyquinoline and remdesivir has been presented. The salient results are (1) higher scoring of antivirals as potential drugs (2) potential of afatinib by scoring as better inhibitor, and (3) biological explanation of the potency of afatinib. Further MD simulations and MM-PBSA calculations showed that afatinib works best to interfere with the the activity of RNA dependent RNA polymerase of SARS-COV-2, thereby inhibiting replication process of single stranded RNA virus. Communicated by Ramaswamy H. Sarma

The recent pandemic caused by SARS-CoV-2 has led the world to a standstill, causing a medical and economic crisis worldwide. This crisis has triggered an urgent need to discover a possible treatment strategy against this novel virus using already-approved drugs. The main protease (Mpro) of this virus plays a critical role in cleaving the translated polypeptides that makes it a potential drug target against COVID-19. Taking advantage of the recently discovered three-dimensional structure of Mpro, we screened approved drugs from the Drug Bank to find a possible inhibitor against Mpro using computational methods and further validating them with biochemical studies. The docking and molecular dynamics study revealed that DB04983 (denufosol) showed the best glide docking score,-11.884 kcal/mol, and MM-PBSA binding free energy,-10.96 kcal/mol. Cobicistat, cangrelor (previous computational studies in our lab), and denufosol (current study) were tested for the in vitro inhibitory effects on Mpro. The IC50 values of these drugs were â 6.7 μM, 0.9 mM, and 1.3 mM, respectively, while the values of dissociation constants calculated using surface plasmon resonance were â 2.1 μM, 0.7 mM, and 1.4 mM, respectively. We found that cobicistat is the most efficient inhibitor of Mpro both in silico and in vitro. In conclusion, cobicistat, which is already an FDA-approved drug being used against HIV, may serve as a good inhibitor against the main protease of SARS-CoV-2 that, in turn, can help in combating COVID-19, and these results can also form the basis for the rational structure-based drug design against COVID-19. CA extern

The recent outbreak of the SARS-CoV-2 virus leading to the disease COVID 19 has become a global pandemic that is spreading rapidly and has caused a global health emergency. Hence, there is an urgent need of the hour to discover effective drugs to control the pandemic caused by this virus. Under such conditions, it would be imperative to repurpose already known drugs which could be a quick and effective alternative to discovering new drugs. The main protease (Mpro) of SARS-COV-2 is an attractive drug target because of its essential role in the processing of the majority of the non-structural proteins which are translated from viral RNA. Herein, we report the high-throughput virtual screening and molecular docking studies to search for the best potential inhibitors against Mpro from FDA approved drugs available in the ZINC database as well as the natural compounds from the Specs database. Our studies have identified six potential inhibitors of Mpro enzyme, out of which four are commercially available FDA approved drugs (Cobicistat, Iopromide, Cangrelor, and Fortovase) and two are from Specs database of natural compounds (Hopeaphenol and Cyclosieversiodide-A). While Cobicistat and Fortovase are known as HIV drugs, Iopromide is a contrast agent and Cangrelor is an anti-platelet drug. Furthermore, molecular dynamic (MD) simulations using GROMACS were performed to calculate the stability of the top-ranked compounds in the active site of Mpro. After extensive computational studies, we propose that Cobicistat and Hopeaphenol show potential to be excellent drugs that can form the basis of treating COVID-19 disease. Communicated by Ramaswamy H. Sarma

Understanding the role of base pairing and stacking displayed by polynucleotide chains interwind together resulting in a double-helical B-DNA type structure is crucial to gaining access to the sophisticated structural arrangement of DNA. Several computational and experimental studies hinted towards the dominance of base pairing over stacking for duplex stability. To find out how significant the individual Watson-Crick hydrogen bonds are in maintaining the double-helical integrity of the DNA, in the present article, we selectively switched off the hydrogen bonds (one specific bond or their combinations in all the base pairs at a time) via manipulating the force fields for A-T and G-C base pairs. We studied 12 systems in total via all-atom explicit-solvent molecular dynamics simulations (200 ns each). The MD output structures were compared with the control system by means of structural, dynamic, and energetic properties to monitor the overall consequences of removing H-bond(s) on the B-DNA characteristics of the model systems. Our findings suggest that all the individual hydrogen bonds involved in base pairing are vital for maintaining the DNA structural integrity as any possible alteration in Watson-Crick hydrogen bond(s) leads to the disintegration/collapse of DNA strands resulting in unfolded states.

Kinetochores are multi-subunit protein assemblies that link chromosomes to microtubules of the mitotic and meiotic spindle. It is still poorly understood how efficient, centromere-dependent kinetochore assembly is accomplished from hundreds of individual protein building blocks in a cell cycle-dependent manner. Here, by combining comprehensive phosphorylation analysis of native Ctf19CCAN subunits with biochemical and functional assays in the model system budding yeast, we demonstrate that Cdk1 phosphorylation activates phospho-degrons on the essential subunit Ame1CENP-U, which are recognized by the E3 ubiquitin ligase complex SCF-Cdc4. Gradual phosphorylation of degron motifs culminates in M-phase and targets the protein for degradation. Binding of the Mtw1Mis12 complex shields the proximal phospho-degron, protecting kinetochore-bound Ame1 from the degradation machinery. Artificially increasing degron strength partially suppresses the temperature sensitivity of a cdc4 mutant, while overexpression of Ame1-Okp1 is toxic in SCF mutants, demonstrating the physiological importance of this mechanism. We propose that phospho-regulated clearance of excess CCAN subunits facilitates efficient centromere-dependent kinetochore assembly. Our results suggest a novel strategy for how phospho-degrons can be used to regulate the assembly of multi-subunit complexes.

Protein-DNA interactions are of great biological importance. The specificity and strength of these intimate contacts are crucial in the proper functioning of a cell, wherein the role of DNA dynamic bendability has been a matter of discussion. We relate DNA bendability to protein binding by introducing some simple modifications in the DNA structure. We removed C5′ carbon in first modified structure and the second has an additional carbon between C3′ and 3′-OH, hereby pronounced as C(−) and C(+) nucleic acids respectively. We observed that C(+) nucleic acid retains B-DNA duplex as seen by means of 500 ns long molecular dynamics (MD) simulations, structural and energetic calculations, while C(−) nucleic acid attains a highly bend structure. We transferred these observations to a protein-DNA system in order to monitor as to what extent the bendability enhances the protein binding. The energetics of binding is explored by performing 100 ns long MD simulations on control and modified DNA-protein complexes followed by running MM-PBSA/GBSA calculations on the resultant structures. It is observed that C(+) nucleic acid has protein binding in close correspondence to the control system (∼−14 kcal/mol) due to their relatable structure, while the C(−) nucleic acid displayed high binding to the protein (∼−18 kcal/mol). DelPhi based calculations reveal that the high binding could be the result of enhanced electrostatic interactions caused by exposed bases in the bend structure for protein recognition. Such modified oligonucleotides, due to their improved binding to protein and resistance to nuclease degradation, have a great therapeutic value.

Synthesis of novel triazole fused iminocyclitol-δ-lactams is described. The synthetic sequence involves the intermolecular [3 + 2] cycloaddition reaction of five-membered iminocyclitol derived azides with diethylacetylene dicarboxylate followed by intramolecular lactamisation, decarboxylation/reduction and final deprotection. Compound 3 is found to be a selective inhibitor of α-glucosidase from baker's yeast while two other compounds (2 and 4) that possess an additional hydroxymethyl group in the triazole ring are selective against β-galactosidase from E. coli. Docking studies suggest the significance of the lactam carbonyl group for effective binding of these inhibitors with the active sites through hydrogen bonding.

Nucleic acids are one of the most enigmatic biomolecules crucial to several biological processes. Nucleic acid-protein interactions are vital for the coordinated and controlled functioning of a cell, leading to the design of several nucleoside/nucleotide analogues capable of mimicking these interactions and hold paramount importance in the field of drug discovery. Purine nucleoside phosphorylase is a well-established drug target due to its association with numerous immunodeficiency diseases. Here, we study the binding of human purine nucleoside phosphorylase (PNP) to some bidirectional symmetric nucleosides, a class of nucleoside analogues that are more flexible due to the absence of sugar pucker restraints. We compared the binding energies of PNP-symmetric nucleosides to the binding energies of PNP-inosine/Imm-H (a transition-state analogue), by means of 200 ns long all-atom explicit-solvent Gaussian accelerated molecular dynamics simulations followed by energetics estimation using the MM-PBSA methodology. Quite interestingly, we observed that a few symmetric nucleosides, namely, ν3 and ν4, showed strong binding with PNP (-14.1 and -12.6 kcal/mol, respectively), higher than inosine (-6.3 kcal/mol) and Imm-H (-9.6 kcal/mol). This is rationalized by an enhanced hydrogen-bond network for symmetric nucleosides compared to inosine and Imm-H while maintaining similar van der Waals contacts. We note that the chemical structures of both ν3 and ν4, due to an additional unsaturation in them, resemble enzymatic transition states and fall in the category of transition-state analogues (TSAs), which are quite popular.

The problem of antibiotic resistance has prompted researchers around the globe to search for new antimicrobial agents. Antimicrobial proteins and peptides are naturally secreted by almost all the living organisms to fight infections and can be safer alternatives to chemical antibiotics. Lactoferrin (LF) is a known antimicrobial protein present in all body secretions. In this study, LF was digested by trypsin, and the resulting hydrolysates were studied with respect to their antimicrobial properties. Among the hydrolysates, a 21-kDa basic fragment of LF (termed lactosmart) showed promise as a new potent antimicrobial agent. The antimicrobial studies were performed on various microorganisms including Shigella flexneri, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli as well as fungal pathogens such as Candida albicans, Candida tropicalis, and Candida glabrata. In addition, the lipopolysaccharide (LPS)-binding properties of lactosmart were studied using surface plasmon resonance technique in vitro, along with docking of LPS and molecular dynamics (MD) simulation studies. The results showed that lactosmart had better inhibitory effects against pathogenic microorganisms compared to LF. The results of docking and MD simulation studies further validated the tighter binding of LPS to lactosmart compared to LF. The two LPS-binding sites have been characterized structurally in detail. Through these studies, it has been demonstrated that in native LF, only one LPS-binding site remains exposed due to its location being on the surface of the molecule. However, due to the generation of the lactosmart molecule, the second LPS-binding site gets exposed too. Since LPS is an essential and conserved part of the bacterial cell wall, the pro-inflammatory response in the human body caused by LPS can be targeted using the newly identified lactosmart. These findings highlight the immense potential of lactosmart in comparison to native LF in antimicrobial defense. We propose that lactosmart can be further developed as an antibacterial, antifungal, and antibiofilm agent.

Deoxyribonucleic acid (DNA) not only stores genetic information but also emerged as a popular drug target. Modified nucleotides/nucleosides have been extensively studied in recent years wherein the sugar/nucleobase/phosphate-backbone has been altered. Several such molecules are FDA approved, capable of targeting nucleic acids and proteins. In this article, we modified negatively charged phosphate backbone to marshall's acid-based neutral backbone and analyzed the resultant structures by utilizing Gaussian accelerated molecular dynamics simulations (1 μs) in aqueous media at 150 mM salt concentration. We noted that the double-helical marshall's nucleic acid structure was partially denatured during the course of simulations, however, after using conformationally locked sugar, the marshall's nucleic acid (hereby called MNA) maintained the double-helical structure throughout the simulations. Despite the fact that MNA has a more extended backbone than the regular DNA, surprisingly, both showed similar helical rise (~3.4 A) along with a comparable Watson-Crick hydrogen bond profile. The backbone difference was majorly compensated in terms of helical twist (~56° (MNA) and ~ 35° (control DNA)). Further, we examined a few MNA based ss-dinucleotides as intercalating ligands for a regular B-DNA. Quite strikingly, the ligands unwinded the DNA and showed intercalating properties with high DNA binding affinities. Hence, the use of small fragments of MNA based molecules in DNA targeted drug discovery is foreseen.

Kinetochores are multi-subunit protein assemblies that link chromosomes to microtubules of the mitotic and meiotic spindle. How effective, yet strictly centromere-dependent kinetochore assembly is coupled to cell cycle progression is incompletely understood. Here, by combining comprehensive phosphorylation analysis of native Ctf19CCANsubunits with biochemical and functional assays in the model system budding yeast, we demonstrate that Cdk1 phosphorylation activates phospho-degrons on the essential subunit Ame1CENP-Uwhich are recognized by the E3 ubiquitin ligase complex SCF-Cdc4. Gradual phosphorylation of degron motifs culminates in M-Phase and targets the protein for degradation. Binding of the Mtw1 complex shields the proximal phospho-degron, protecting kinetochore-bound Ame1 from the degradation machinery. Artificially increasing degron strength partially suppresses the temperature-sensitivity of acdc4mutant, while overexpression of Ame1-Okp1 is toxic to cells, demonstrating the physiological importance of this mechanism. We propose that phospho-regulated clearance of excess CCAN subunits protects against ectopic kinetochore assembly and contributes to mitotic checkpoint silencing. Our results suggest a novel strategy for how phospho-degrons can be used to regulate the assembly of multi-subunit complexes.

DNA has been an attractive target for anticancer, antitumor agents and antibiotics. While the growing number of DNA-drug complexes in structural repositories are yielding molecular insights on DNA-drug recognition principles, identification of distinct sequence-specific electrostatic potentials in the minor and major grooves of DNA has aroused keen interest in designing/identifying molecules which can bind to DNA in a sequence-specific manner. Computational protocols for examining such interactions by means of docking small molecules in the grooves of DNA are accessible. However, with the present compute-intensive docking and scoring protocols, it is nearly impossible to scan millions of molecules for DNA targeted drug discovery. This makes it necessary to develop a rapid screening protocol for scanning millions of molecules to identify potential binders to any DNA sequence of choice. RASDD (RApid Screening of DNA-Drug) is one such utility which utilizes physicochemical properties associated with DNA as well as groove binders to rapidly scan a large library of molecules. The methodology is developed using 30 DNA-drug complexes (R = 0.85) and, when tested on 18 DNA-drug complexes, yielded a correlation (R) of 0.83 between experimental and predicted binding free energies. With RASDD protocol, it is possible to scan a million compounds against a DNA sequence of interest (AT-rich) in ~18s! RASDD is freely accessible at http://www.scfbio-iitd.res.in/software/drugdesign/rasdd.jsp.

Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T

DNA triplex is a popular, higher-order structural arrangement with several biological importance. In the present article, we examined the impact of replacing regular deoxyribose sugar by conformationally locked sugar on the structure/stability of a DNA triplex. We individually modified single strands of DNA triplex (3′-5′ strand/5′-3′ strand) and observed the consequences in terms of the overall structural integrity and energetics using all-atom explicit-solvent Gaussian accelerated molecular dynamics simulations at biological salt concentration. As anticipated, the control DNA triplex maintained the structural integrity throughout the simulations. However, it is striking to note that a duplex evolved from both the modified systems (3′-5′ modified triplex as well as 5′-3′ modified triplex). The resultant duplexes in both cases contain a modified strand and a regular strand, whereas the third strand (regular ssDNA) left the binding site entirely. We observed that the modified ssDNA binds to the regular ssDNA with high affinities in both the hybrid duplexes (∼−64 kcal/mol), significantly higher than the regular ssDNA – regular ssDNA interaction (∼−52 kcal/mol). The remarkable binding of modified ssDNA to regular ssDNA can be utilized to design new antisense oligonucleotides, and the role of such modified oligonucleotides in anticancer therapy is foreseen.

The recent outbreak of the SARS-CoV-2 virus leading to the disease COVID 19, a global pandemic has resulted in an unprecedented loss of life and economy worldwide. Hence, there is an urgent need to discover effective drugs to control this pandemic. NSP16 is a methyltransferase that methylates the ribose 2'-O position of the viral nucleotide. Taking advantage of the recently solved structure of NSP16 with its inhibitor, S-Adenosylmethionine, we have virtually screened FDA approved drugs, drug candidates and natural compounds. The compounds with the best docking scores were subjected to molecular dynamics simulations followed by binding free energy calculations using the MM-PBSA method. The known drugs which were identified as potential inhibitors of NSP16 from SARS-CoV-2 included DB02498, DB03909, DB03186, Galuteolin, ZINC000029416466, ZINC000026985532, and ZINC000085537017. DB02498 (Carba-nicotinamide-adenine-dinucleotide) is an approved drug which has been used since the late 1960s in intravenous form to significantly lessen withdrawal symptoms from a variety of drugs and alcohol addicts and it has the best MM-PBSA binding free energy of-12.83 ± 0.52 kcal/mol. The second best inhibitor, Galuteolin is a natural compound that inhibits tyrosinase enzyme with MM-PBSA binding free energy value of -11.21 ± 0.47 kcal/mol. Detailed ligand and protein interactions were analyzed and common residues across SARS-CoV, SARS-CoV-2, and MERS-CoV were identified. We propose Carba-nicotinamide-adenine-dinucleotide and Galuteolin as the potential inhibitors of NSP16. The results in this study can be used for the treatment of COVID-19 and can also form the basis of rational drug design against NSP16 of SARS-CoV-2.

This paper proposes a control structure for a bidirectional battery charger using a three-phase PWM ac/dc converter and a resonant CLLC dc/dc converter. The proposed control system with a staged architecture focuses on improving the power quality and minimizing total harmonic distortion of the system. A variable frequency hysteresis control system along with a current control loop is employed for the ac/dc converter for the fast charging phase of the battery. For optimal performance, the CLLC converter is designed to operate at the resonant frequency. Simulation results obtained using PLECS simulation software are presented to validate the performance of the proposed control system.

A mixed affinity dimeric radioligand 99mTc-(BTZ)2DTPA was designed using a “bivalent ligand approach” and evaluated as an SPECT imaging agent for targeting 5-HT1A/5-HT7 dimeric receptors in the central nervous system. In silico studies reflected high affinity for dimeric 5-HT1A/5-HT7 receptors. Following multi-step synthesis, the ligand was obtained in 87.5% yield. Detailed physico-chemical analysis included pKa evaluation and optimization of radiolabeling parameters (>98% radiolabeling efficiency). The in vitro serum-stability test of the 99mTc-complex showed ≤8.7% dissociation and appreciable stability when challenged with excess cysteine (≤4.4% dissociation). Cyto-compatibility (4.8–0.6% cell death at 100 μM to 1 pM) and haemo-compatibility (1.05% erythrocyte destruction) suggested optimum biocompatibility. Blood kinetics revealed biphasic clearance. The brain/blood ratio of 0.66 assured the CNS penetration ability and BBB permeability of the developed radioligand. Bio-distribution and in vivo SPECT imaging revealed a maximum brain uptake of 2.08 ± 0.08% ID per g at 10 min p.i. followed by major activity accumulation in 5-HT1A/5-HT7 receptor-rich regions viz., the hippocampus (41.83% ID per g) and the cortex (23.56% ID per g) of mouse brains ascertaining selective targeting of 99mTc-(BTZ)2DTPA. The radiotracer was excreted majorly through the renal route. These preclinical studies reveal that the 99mTc-(BTZ)2DTPA radiotracer shows promise as an effective diagnostic agent for neurological disorders.

DNA displays directional asymmetry (5’→3’), a fundamental property associated with each strand of the nucleic acids and is crucial to several biological processes such as transcription and replication. We observe that this asymmetry can be altered by a number of ways leading to directionally symmetric nucleic acids. We report six such approaches for the creation of symmetric backbones, their insertion in a regular B-DNA structure followed by their characterization using molecular dynamics (MD) simulations on a microsecond timescale in explicit solvent. We compared the resultant MD structures of symmetric nucleic acids with that of regular B-DNA in terms of helicoidal parameters, dihedrals, groove geometry, and solvent/ions accessibility. We also compared the Watson-Crick hydrogen bond strength of these symmetric molecules to that of the control B-DNA system. It was found that the symmetric DNAs with a few substituents designed retained the double helical B-DNA type structure as seen by means of structural and energetic parameters. As an application of such symmetric molecules, we evaluated the binding free energies of single stranded symmetric nucleic acids with a short stretch of complementary RNA and found that a few molecules designed have comparable energies to that of control DNA-RNA hybrid system. As the chemical modifications in the oligonucleotides have been a remarkable tool for control over the nucleotide properties, mainly the nucleotide bending, binding to RNA targets, and stability to nucleases to design nucleoside drug analogs; the importance of the proposed symmetric molecules in these areas is foreseen. Communicated by Ramaswamy H. Sarma

Summarizing cricket matches is a labor intensive task that demands a certain level of proficiency. The paper proposes a novel method for automatically detecting and summarizing important events in a cricket match. Our model takes into input the video recording of the entire cricket match and returns the most important clips of the game as the output. Techniques like optical character recognition, sound detection and replay detection have been used to extract important events such as boundaries, wickets and other playfield scenarios in a cricket match. These events are then clipped together to form the entire highlight for the cricket match. We performed several qualitative and quantitative experiments to evaluate our model. Our model achieves an accuracy of 89.45% to detect events like wickets, fours and sixes which indicates the usefulness of the model in real life scenarios.

The dual role of D-mannose as a ligand for Pd catalyzed cross-coupling, and as a hydrogen source for nitro reduction is demonstrated in a modular cross coupling-nitro reduction sequence. The synthetic utility and generality of this green protocol has been illustrated by the synthesis of 20 aminobiphenyl and 10 aminostilbene derivatives in high yields through a one-pot Suzuki coupling-nitro reduction and a Heck coupling-nitro reduction, respectively, starting from halonitroarenes as substrates.

Asymmetry (5'→3') associated with each strand of the deoxyribonucleic acid (DNA) is inherent in the sugar-phosphate backbone connectivity and is essential for replication and transcription. We note that this asymmetry is due to one single chemical bond (C3' to C2' ) in each nucleotide unit, and the absence of this bond results in directionally symmetric nucleic acids. We also discovered that creation of an extra chemical bond (C5' to C2' ) can lead to a symmetric backbone. Keeping their potential synthetic and therapeutic interest in mind, we designed a few novel symmetric nucleic acids. We investigated their conformational stability and flexibility via detailed all atom explicit solvent 100-ns long molecular dynamics simulations and compared the resulting structures with that of regular B-DNA. Quite interestingly, some of the symmetric nucleic acids retain the overall double helical structure indicating their potential for integration in physiological DNA without causing major structural perturbations.

The conformation of DNA plays an important role in its chemical and biological function as well as for its potential applications in nanotechnology1. Different conformations of DNA exhibit distinct values for the conductance2. Such a distinct conductance can also be used to detect the conformation. DNA mainly adopts A and B conformations at lower and higher hydration levels, respectively1,2. Experimental and theoretical studies suggest that A to B transformation is smooth and continuous1, whereas B to A transition is sequence specific, cooperative, and reversible3,4. To the best of our knowledge, there is no experimental method that can precisely evaluate the electronic structure of DNA during its conformation transition. A recent theoretical study discusses the change in electronic properties during the transformation1. A recent work found an unexpected result that A-DNA conducts better than B-DNA. To provide insight into the time evolution of the electronic properties during change in conformation, we present a computational investigation of the electrical conductance of 3’-CCCGCGCCC-5’ DNA during various time step of the MD trajectory as the molecule undergoes A to B transition. The initial structure of A-DNA is built using nucleic acid builder (NAB) in AMBER15. For DNA, the parmbsc1 force field is used and SPC/E force field is used for water and ions. The negative charge on DNA backbone is neutralized with sodium (Na) ions. Additionally, Na+ and Cl- ions are added to achieve 150mM salt concentration. For A to B DNA transformation, A-DNA is placed in water. Further minimization and equilibration is performed according to ABC Minimization5. 50 ns molecular dynamics (MD) trajectory is generated with particle mesh Ewald (PME) algorithm and periodic boundary condition (PBC) under constant pressure (isobaric-isothermal ensemble). The transformed B-DNA at the end of 50ns simulation is then placed in 85%ethanol+15%water with 150mM of salt concentration. Packmol is used to model the 85%ethanol+15%water solvent. The temperature is increased to 325K and the simulation is continued for another 48ns. The snapshots during A to B transformations (at 1ps, 50 ps, 100ps, 125ps, 150ps, 200ps and 50000ps, respectively) are considered for electronic structure calculations, where the DNA encounters major structural changes (also done for B to A transformation). Density Functional Theory (DFT) calculations are performed on these structures using GAUSSIAN 09, with the B3LYP functional and 6-31G(d,p) basis set. The electrical conductance of DNA is determined using Landauer formalism with Non-equilibrium Green's function approach2. Figure 1 (a) shows the sugar pucker in the range of 0o-36o (representing A-DNA) in the initial phase of simulation that increases step by step to 140o-180o (representing B-DNA) and remains in that range till 50ns. We also find that the rise per base pairs increases from ~2.6Å to ~3.4 Å and twist increases from 30-34 Å to 35-38 Å, which confirm the transformation. We could reverse this transformation when the B-DNA is placed in 85%ethanol+15%water at 325K (results not presented here). A-DNA at 1ps has HOMO at -5.04eV and LUMO at -1.04eV. During the transformation, mean value of HOMO energy is -5.06eV and that of LUMO is -1.21eV, indicating significant change in the LUMO energy (~20%). We next look at the charge transport during the transformation, i.e. for the frames at 1 ps, 50 ps, 100 ps, 125 ps, 150ps, 200ps and 50000ps. Overall conductance is seen to decrease (increase) with the A(B) to B(A) transformation (Figure 1 (b) for A to B transformation). It is to be noted that this is the same DNA sequence investigated experimentally2 for which the A-conformation exhibits higher conductance than B-conformation. Our simulations clearly verify these experimental findings and provide further information on the evolution of conductance with time. The fluctuations in between could be related to the spatial configurations of counterions, which can alter the conductance of DNA6. References 1 H. Wang, T.E. Cheatham, P.M. Gannett, and J.P. Lewis, Soft Matter 5, 685 (2009). 2 J.M. Artés, Y. Li, J. Qi, M.P. Anantram, and J. Hihath, Nat. Commun. 6, (2015). 3 J.T. Waters, X.-J. Lu, R. Galindo-Murillo, J.C. Gumbart, H.D. Kim, T.E. Cheatham, and S.C. Harvey, J. Phys. Chem. B 120, 8449 (2016). 4 M. Kulkarni and A. Mukherjee, Prog. Biophys. Mol. Biol. 128, 63 (2017). 5 M. Pasi, J.H. Maddocks, D. Beveridge, T.C. Bishop, D.A. Case, I.I.I.T. Cheatham, P.D. Dans, B. Jayaram, F. Lankas, C. Laughton, J. Mitchell, R. Osman, M. Orozco, A. Pérez, D. Petkevičiūtė, N. Spackova, J. Sponer, K. Zakrzewska, and R. Lavery, Nucleic Acids Res. 42, 12272 (2014). 6 R.N. Barnett, C.L. Cleveland, A. Joy, U. Landman, and G.B. Schuster, Science (80-. ). 294, 567 (2001). Figure 1

The dual role of D-mannose as ligand for the Pd-catalyzed cross-coupling and as hydrogen source for the nitro reduction is demonstrated.