655-662Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family ... more 655-662Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family of ribosome inactivating proteins (RIPs), which bind to the rRNA of ribosomes to inactivate them. Curcin is a type 2 RIP protein consisting of a single chain. Its presence makes it difficult to utilize the Jatropha seed cakes for animal feed. Inhibition of its biological activity against ribosomes through mutagenesis of protein structure is a novel and valid approach to understand its mode of action. Such mutations were introduced into the protein sequence and the protein was modeled to see their effect on interaction with GAGA loop of mouse 28S rRNA. Interestingly, with the removal or mutation of critical residues of the active site, the binding of curcin and rRNA molecule increased thus indicating towards the steric hindrance provided by these residues. The removal of these residues seems to increase the cavity size, thus, making it easier for the approaching rRNA molecule to bind clos...
The hinge-like movement of the SCCH domain upon ligand binding closes the ubiquitin binding site ... more The hinge-like movement of the SCCH domain upon ligand binding closes the ubiquitin binding site and disrupts the interfaces crucial for thioester bond formation.
Peptaibols are short peptides of fungal origin produced by non-ribosomal peptide synthetases (NRP... more Peptaibols are short peptides of fungal origin produced by non-ribosomal peptide synthetases (NRPS) and are known to have interesting biological properties including pore formation in bilayer membranes which imparts them antibacterial, antifungal and sometimes antiviral properties. They have also been shown to elicit plant resistance mechanisms. Peptaibols are characterized by non-standard amino acid content like aminoisobutyric acid (Aib), D-isovaline, an acetylated N-terminal and a C-terminal amino-alcohol (e.g. valinol). Given the interesting and promising nature of these peptides, an optimized extraction and purification procedure along with primary structure determination by HPLC-ESI-MS was carried out in the case of the peptaibols produced by the mushroom green mould pathogens Trichoderma pleuroti and T. aggressivum f. europaeum. The three-dimensional structure of a new hypomurocin-like peptaibol detected in T. aggressivum was elucidated using 100 ns long molecular dynamics simulation based on Amber14 force fields and parameterization of non-standard amino acid residues Aib, D-isovaline and C-terminal valinol. The simulated structure shows formation of helical motifs with a break introduced by proline as expected from this class of molecules. The N- and C-terminals are the most variable regions which might have an implication in membrane binding and function. All Aib residues show an alternating left-handed and right-handed alpha helix formation throughout the trajectory owing to its achiral nature but the presence of other residues like leucine, glutamine and valine shift the whole structure towards a right-handed conformation. This study is the stepping stone for establishing a structure-activity relationship for this class of molecules which, in turn, may help in their possible exploitation as therapeutics or agricultural agents.
Chemosensory perception in insects involves a broad set of chemosensory proteins (CSPs) that iden... more Chemosensory perception in insects involves a broad set of chemosensory proteins (CSPs) that identify the bouquet of chemical compounds present in the external environment and regulate specific behaviors. The current study is focused on the Spodoptera litura (Fabricius) chemosensory-related protein, SlitCSP3, a midgut-expressed CSP, which demonstrates differential gene expression upon different diet intake. There is an intriguing possibility that SlitCSP3 can perceive food-derived chemical signals and modulate insect feeding behavior. We predicted the three-dimensional structure of SlitCSP3 and subsequently performed an accelerated molecular dynamics (aMD) simulation of the best-modeled structure. SlitCSP3 structure has six α-helices arranged as a prism and a hydrophobic binding pocket predominated by leucine and isoleucine. We analyzed the interaction of selected host plant metabolites with the modeled structure of SlitCSP3. Out of two predicted binding pockets in SlitCSP3, the pla...
2015 2nd International Conference on Computing for Sustainable Global Development (INDIACom), 2015
Fusarium circinatum is a disease-causing fungal agent responsible for pitch canker disease in pin... more Fusarium circinatum is a disease-causing fungal agent responsible for pitch canker disease in pine trees. In this study, the cytochrome b protein which plays an important role in electron transport chain for respiration is taken as a crucial target for developing anti-fungal inhibitors. We predicted the protein model of cytochrome b in Fusarium circinatum based on the Saccharomyces cytochrome b template. The A-chain of cytochrome b in Fusarium circinatum is identical to the N-chain of cytochrome b of Saccharomyces cerevisiae. The modeled cytochrome b structure was used to screen ZINC database compounds through DOCKBlaster which yielded 200 top scoring compounds. We report the top two compounds namely, ZINC53798 and ZINC18029019 which can be further evaluated for their anti-fungal activities through experimental means. The binding affinity scores for these two are -37.75 and -37.09 kcal/mol respectively. They are expected to inhibit the function of cytochrome b at the ubiquinol bindi...
Transcription factors (TFs) are proteins that bind to DNA and activate or repress gene expression... more Transcription factors (TFs) are proteins that bind to DNA and activate or repress gene expression at the transcriptional level. Ethylene-Responsive Element Binding Protein (EREBP) represents one such class of DNA binding proteins/TFs. In the present study, EREBP-1 gene of Glycine max was selected to find out similar genes in Phaseolus vulgaris, Arabidopsis thaliana and Cucumis sativus dicot plants by taking their protein sequences. A combined phylogenetic tree was constructed, which yielded four EREBP subgroups. From each subgroup, one protein sequence was evaluated, which had highest Bits (score) and lowest E-value. Consequently, two EREBPs of P. vulgaris and two of C. sativus were chosen from the four subgroups of the phylogenetic tree. Four EREBP structures were then modelled using ab initio based approach and were energy minimized. They were validated on the basis of Ramachandran plot analysis, where residues were in most favored region ranging from 75.8087.70%. Further, intrins...
Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family of ribo... more Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family of ribosome inactivating proteins (RIPs), which bind to the rRNA of ribosomes to inactivate them. Curcin is a type 2 RIP protein consisting of a single chain. Its presence makes it difficult to utilize the Jatropha seed cakes for animal feed. Inhibition of its biological activity against ribosomes through mutagenesis of protein structure is a novel and valid approach to understand its mode of action. Such mutations were introduced into the protein sequence and the protein was modeled to see their effect on interaction with GAGA loop of mouse 28S rRNA. Interestingly, with the removal or mutation of critical residues of the active site, the binding of curcin and rRNA molecule increased thus indicating towards the steric hindrance provided by these residues. The removal of these residues seems to increase the cavity size, thus, making it easier for the approaching rRNA molecule to bind closely. Ho...
Soil Biological Communities and Ecosystem Resilience, 2017
Filamentous fungi are producers of a large number of secondary metabo lites with wide spectra of ... more Filamentous fungi are producers of a large number of secondary metabo lites with wide spectra of biological effects. Among them, peptaibols represent a group of compounds produced mainly by members of the mycotrophic filamentous fungal genus Trichoderma. A simple peptaibol characterization strategy including purification and structural elucidation steps was applied to examine the peptaibol production of three strains from the Longibrachiatum section of genus Trichoderma, T. aethiopicum TUCIM 1817, T. novae-zelandiae TUCIM 4158 and T. pseudokon ingii TUCIM 1277, all deriving from natural forest habitats (disturbed semiforest, native Notophagus forest and the bark of Beilschmiedia tawa, respectively). After the solid phase clean-up of culture extracts, mass spectrometric analysis of peptai bols produced by the examined strains was performed by on-line reversed-phase
Alzheimer’s (AD) is the leading cause of dementia among elderly people. Considering the complex h... more Alzheimer’s (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression.β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BAC...
Plant defensins possess diverse biological functions that include antifungal and antibacterial ac... more Plant defensins possess diverse biological functions that include antifungal and antibacterial activities and α-amylase and trypsin inhibitory properties. Two mutations, G9R and V39R, were confirmed to increase the antifungal activity ofRaphanus sativusantifungal protein 2 (RsAFP2). Accelerated Molecular Dynamics (aMD) were carried out to examine the conformational changes present in these RsAFP2 mutants, and its two closest homologs compared to the wild-type protein. Specifically, the root mean square fluctuation values for the eight cysteine amino acids involved in the four disulfide bonds were low in the V39R mutant compared to the wild-type. Additionally, analysis of the free energy change revealed that G9R and V39R mutations exert a neutral and stabilizing effect on RsAFP2 conformation, and this is supported by the observed lower total energy of mutants compared to the wild-type, suggesting that enhanced stability of the mutants. However, MD simulations to a longer time scale w...
The use of enhanced sampling molecular dynamics simulations to facilitate the folding of proteins... more The use of enhanced sampling molecular dynamics simulations to facilitate the folding of proteins is a relatively new approach which has quickly gained momentum in recent years. Accelerated molecular dynamics (aMD) can elucidate the dynamic path from the unfolded state to the near-native state, “flattened” by introducing a non-negative boost to the potential. Alamethicin F30/3 (Alm F30/3), chosen in this study, belongs to the class of peptaibols that are 7–20 residue long, non-ribosomally synthesized, amphipathic molecules that show interesting membrane perturbing activity. The recent studies undertaken on the Alm molecules and their transmembrane channels have been reviewed. Three consecutive simulations of ~900 ns each were carried out where N-terminal folding could be observed within the first 100 ns, while C-terminal folding could only be achieved almost after 800 ns. It took ~1 μs to attain the near-native conformation with stronger potential boost which may take several μs wor...
Peptaibols are a special class of fungal peptides with an acetylated N-terminus and a C-terminal ... more Peptaibols are a special class of fungal peptides with an acetylated N-terminus and a C-terminal 1,2-amino alcohol along with non-standard amino acid residues. New peptaibols named tripleurins were recently identified from a strain of the filamentous fungal species Trichoderma pleuroti, which is known to cause green mould disease on cultivated oyster mushrooms. To understand the mode of action of these peptaibols, the three-dimensional structure of tripleurin (TPN) XIIc, an 18-mer peptide, was elucidated using an enhanced sampling method, accelerated MD, in water and chloroform solvents. Non-standard residues were parameterized by the Restrained Electrostatic Potential (RESP) charge fitting method. The dihedral distribution indicated towards a right-handed helical formation for TPN XIIc in both solvents. Dihedral angle based principal component analysis revealed a propensity for a slightly bent, helical folded conformation in water solvent, while two distinct conformations were reve...
A major genetic suspect for Alzheimer’s disease is the pathological conformation assumed by apoli... more A major genetic suspect for Alzheimer’s disease is the pathological conformation assumed by apolipoprotein E4 (ApoE4) through intramolecular interaction. In the present study, a large library of natural compounds was screened against ApoE4 to identify novel therapeutic molecules that can prevent ApoE4 from being converted to its pathological conformation. We report two such natural compounds PHC and IAH that bound to the active site of ApoE4 during the docking process. The binding analysis suggested that they have a strong mechanistic ability to correct the pathological structural orientation of ApoE4 by preventing repulsion between Arg 61 and Arg 112, thus inhibiting the formation of a salt bridge between Arg 61 and Glu 255. However, when the molecular dynamics simulations were carried out, structural changes in the PHC-bound complex forced PHC to move out of the cavity thus destabilizing the complex. However, IAH was structurally stable inside the binding pocket throughout the sim...
This study examined the structural diversity and bioactivity of peptaibol compounds produced by s... more This study examined the structural diversity and bioactivity of peptaibol compounds produced by species from the phylogenetically separated Longibrachiatum Clade of the filamentous fungal genus Trichoderma, which contains several biotechnologically, agriculturally and clinically important species. HPLC-ESI-MS investigations of crude extracts from 17 species of the Longibrachiatum Clade (T.
and belong to clade of , the largest and most diverse group of this genus. They produce a wide ra... more and belong to clade of , the largest and most diverse group of this genus. They produce a wide range of bioactive secondary metabolites, including peptaibols with antibacterial, antifungal, and antiviral properties. The unusual amino acid residues of peptaibols, i.e., α-aminoisobutyric acid (Aib), isovaline (Iva), and the C-terminal 1,2-amino alcohol make them unique among peptides. In this study, the peptaibiomes of and were investigated by HPLC-ESI-MS. The examined strains appeared to produce 19-residue peptaibols, most of which are unknown from literature, but their amino acid sequences are similar to those of trikoningins, tricholongins, trichostrigocins, trichorzianins, and trichorzins. A new group of peptaibols detected in are described here under the name "Koningiopsin". Trikoningin KA V, the closest peptaibol compound to the peptaibols produced by these two strains, was selected for structural investigation by short MD simulation, which revealed that many residues ...
International journal of biological macromolecules, Jan 7, 2018
Plants are endowed with an innate immune system, which enables them to protect themselves from pe... more Plants are endowed with an innate immune system, which enables them to protect themselves from pest and pathogen. The participation of pathogenesis-related (PR) proteins is one of the most crucial events of inducible plant defense response. Herein, we report the characterization of CaHaPR-4, a Helicoverpa-inducible class II PR-4 protein from chickpea. Bioinformatic analysis of CaHaPR-4 protein indicated the presence of a signal peptide, barwin domain but it lacks the chitin-binding site/hevein domain. The recombinant CaHaPR-4 is bestowed with RNase and bivalent ion-dependent DNase activity. Further, the RNA and DNA binding sites were identified and confirmed by analyzing interactions between mutated CaHaPR-4 with the altered active site and ribonuclease inhibitor, 5'ADP and DNase inhibitor, 2‑nitro‑5‑thiocyanobenzoic acid (NTCB) using 3D modeling and docking studies. Moreover, CaHaPR-4 shows antifungal activity as well as growth inhibiting properties against neonatal podborer la...
655-662Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family ... more 655-662Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family of ribosome inactivating proteins (RIPs), which bind to the rRNA of ribosomes to inactivate them. Curcin is a type 2 RIP protein consisting of a single chain. Its presence makes it difficult to utilize the Jatropha seed cakes for animal feed. Inhibition of its biological activity against ribosomes through mutagenesis of protein structure is a novel and valid approach to understand its mode of action. Such mutations were introduced into the protein sequence and the protein was modeled to see their effect on interaction with GAGA loop of mouse 28S rRNA. Interestingly, with the removal or mutation of critical residues of the active site, the binding of curcin and rRNA molecule increased thus indicating towards the steric hindrance provided by these residues. The removal of these residues seems to increase the cavity size, thus, making it easier for the approaching rRNA molecule to bind clos...
The hinge-like movement of the SCCH domain upon ligand binding closes the ubiquitin binding site ... more The hinge-like movement of the SCCH domain upon ligand binding closes the ubiquitin binding site and disrupts the interfaces crucial for thioester bond formation.
Peptaibols are short peptides of fungal origin produced by non-ribosomal peptide synthetases (NRP... more Peptaibols are short peptides of fungal origin produced by non-ribosomal peptide synthetases (NRPS) and are known to have interesting biological properties including pore formation in bilayer membranes which imparts them antibacterial, antifungal and sometimes antiviral properties. They have also been shown to elicit plant resistance mechanisms. Peptaibols are characterized by non-standard amino acid content like aminoisobutyric acid (Aib), D-isovaline, an acetylated N-terminal and a C-terminal amino-alcohol (e.g. valinol). Given the interesting and promising nature of these peptides, an optimized extraction and purification procedure along with primary structure determination by HPLC-ESI-MS was carried out in the case of the peptaibols produced by the mushroom green mould pathogens Trichoderma pleuroti and T. aggressivum f. europaeum. The three-dimensional structure of a new hypomurocin-like peptaibol detected in T. aggressivum was elucidated using 100 ns long molecular dynamics simulation based on Amber14 force fields and parameterization of non-standard amino acid residues Aib, D-isovaline and C-terminal valinol. The simulated structure shows formation of helical motifs with a break introduced by proline as expected from this class of molecules. The N- and C-terminals are the most variable regions which might have an implication in membrane binding and function. All Aib residues show an alternating left-handed and right-handed alpha helix formation throughout the trajectory owing to its achiral nature but the presence of other residues like leucine, glutamine and valine shift the whole structure towards a right-handed conformation. This study is the stepping stone for establishing a structure-activity relationship for this class of molecules which, in turn, may help in their possible exploitation as therapeutics or agricultural agents.
Chemosensory perception in insects involves a broad set of chemosensory proteins (CSPs) that iden... more Chemosensory perception in insects involves a broad set of chemosensory proteins (CSPs) that identify the bouquet of chemical compounds present in the external environment and regulate specific behaviors. The current study is focused on the Spodoptera litura (Fabricius) chemosensory-related protein, SlitCSP3, a midgut-expressed CSP, which demonstrates differential gene expression upon different diet intake. There is an intriguing possibility that SlitCSP3 can perceive food-derived chemical signals and modulate insect feeding behavior. We predicted the three-dimensional structure of SlitCSP3 and subsequently performed an accelerated molecular dynamics (aMD) simulation of the best-modeled structure. SlitCSP3 structure has six α-helices arranged as a prism and a hydrophobic binding pocket predominated by leucine and isoleucine. We analyzed the interaction of selected host plant metabolites with the modeled structure of SlitCSP3. Out of two predicted binding pockets in SlitCSP3, the pla...
2015 2nd International Conference on Computing for Sustainable Global Development (INDIACom), 2015
Fusarium circinatum is a disease-causing fungal agent responsible for pitch canker disease in pin... more Fusarium circinatum is a disease-causing fungal agent responsible for pitch canker disease in pine trees. In this study, the cytochrome b protein which plays an important role in electron transport chain for respiration is taken as a crucial target for developing anti-fungal inhibitors. We predicted the protein model of cytochrome b in Fusarium circinatum based on the Saccharomyces cytochrome b template. The A-chain of cytochrome b in Fusarium circinatum is identical to the N-chain of cytochrome b of Saccharomyces cerevisiae. The modeled cytochrome b structure was used to screen ZINC database compounds through DOCKBlaster which yielded 200 top scoring compounds. We report the top two compounds namely, ZINC53798 and ZINC18029019 which can be further evaluated for their anti-fungal activities through experimental means. The binding affinity scores for these two are -37.75 and -37.09 kcal/mol respectively. They are expected to inhibit the function of cytochrome b at the ubiquinol bindi...
Transcription factors (TFs) are proteins that bind to DNA and activate or repress gene expression... more Transcription factors (TFs) are proteins that bind to DNA and activate or repress gene expression at the transcriptional level. Ethylene-Responsive Element Binding Protein (EREBP) represents one such class of DNA binding proteins/TFs. In the present study, EREBP-1 gene of Glycine max was selected to find out similar genes in Phaseolus vulgaris, Arabidopsis thaliana and Cucumis sativus dicot plants by taking their protein sequences. A combined phylogenetic tree was constructed, which yielded four EREBP subgroups. From each subgroup, one protein sequence was evaluated, which had highest Bits (score) and lowest E-value. Consequently, two EREBPs of P. vulgaris and two of C. sativus were chosen from the four subgroups of the phylogenetic tree. Four EREBP structures were then modelled using ab initio based approach and were energy minimized. They were validated on the basis of Ramachandran plot analysis, where residues were in most favored region ranging from 75.8087.70%. Further, intrins...
Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family of ribo... more Curcin is a toxic protein found in the seeds of Jatropha curcas and belongs to the family of ribosome inactivating proteins (RIPs), which bind to the rRNA of ribosomes to inactivate them. Curcin is a type 2 RIP protein consisting of a single chain. Its presence makes it difficult to utilize the Jatropha seed cakes for animal feed. Inhibition of its biological activity against ribosomes through mutagenesis of protein structure is a novel and valid approach to understand its mode of action. Such mutations were introduced into the protein sequence and the protein was modeled to see their effect on interaction with GAGA loop of mouse 28S rRNA. Interestingly, with the removal or mutation of critical residues of the active site, the binding of curcin and rRNA molecule increased thus indicating towards the steric hindrance provided by these residues. The removal of these residues seems to increase the cavity size, thus, making it easier for the approaching rRNA molecule to bind closely. Ho...
Soil Biological Communities and Ecosystem Resilience, 2017
Filamentous fungi are producers of a large number of secondary metabo lites with wide spectra of ... more Filamentous fungi are producers of a large number of secondary metabo lites with wide spectra of biological effects. Among them, peptaibols represent a group of compounds produced mainly by members of the mycotrophic filamentous fungal genus Trichoderma. A simple peptaibol characterization strategy including purification and structural elucidation steps was applied to examine the peptaibol production of three strains from the Longibrachiatum section of genus Trichoderma, T. aethiopicum TUCIM 1817, T. novae-zelandiae TUCIM 4158 and T. pseudokon ingii TUCIM 1277, all deriving from natural forest habitats (disturbed semiforest, native Notophagus forest and the bark of Beilschmiedia tawa, respectively). After the solid phase clean-up of culture extracts, mass spectrometric analysis of peptai bols produced by the examined strains was performed by on-line reversed-phase
Alzheimer’s (AD) is the leading cause of dementia among elderly people. Considering the complex h... more Alzheimer’s (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression.β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BAC...
Plant defensins possess diverse biological functions that include antifungal and antibacterial ac... more Plant defensins possess diverse biological functions that include antifungal and antibacterial activities and α-amylase and trypsin inhibitory properties. Two mutations, G9R and V39R, were confirmed to increase the antifungal activity ofRaphanus sativusantifungal protein 2 (RsAFP2). Accelerated Molecular Dynamics (aMD) were carried out to examine the conformational changes present in these RsAFP2 mutants, and its two closest homologs compared to the wild-type protein. Specifically, the root mean square fluctuation values for the eight cysteine amino acids involved in the four disulfide bonds were low in the V39R mutant compared to the wild-type. Additionally, analysis of the free energy change revealed that G9R and V39R mutations exert a neutral and stabilizing effect on RsAFP2 conformation, and this is supported by the observed lower total energy of mutants compared to the wild-type, suggesting that enhanced stability of the mutants. However, MD simulations to a longer time scale w...
The use of enhanced sampling molecular dynamics simulations to facilitate the folding of proteins... more The use of enhanced sampling molecular dynamics simulations to facilitate the folding of proteins is a relatively new approach which has quickly gained momentum in recent years. Accelerated molecular dynamics (aMD) can elucidate the dynamic path from the unfolded state to the near-native state, “flattened” by introducing a non-negative boost to the potential. Alamethicin F30/3 (Alm F30/3), chosen in this study, belongs to the class of peptaibols that are 7–20 residue long, non-ribosomally synthesized, amphipathic molecules that show interesting membrane perturbing activity. The recent studies undertaken on the Alm molecules and their transmembrane channels have been reviewed. Three consecutive simulations of ~900 ns each were carried out where N-terminal folding could be observed within the first 100 ns, while C-terminal folding could only be achieved almost after 800 ns. It took ~1 μs to attain the near-native conformation with stronger potential boost which may take several μs wor...
Peptaibols are a special class of fungal peptides with an acetylated N-terminus and a C-terminal ... more Peptaibols are a special class of fungal peptides with an acetylated N-terminus and a C-terminal 1,2-amino alcohol along with non-standard amino acid residues. New peptaibols named tripleurins were recently identified from a strain of the filamentous fungal species Trichoderma pleuroti, which is known to cause green mould disease on cultivated oyster mushrooms. To understand the mode of action of these peptaibols, the three-dimensional structure of tripleurin (TPN) XIIc, an 18-mer peptide, was elucidated using an enhanced sampling method, accelerated MD, in water and chloroform solvents. Non-standard residues were parameterized by the Restrained Electrostatic Potential (RESP) charge fitting method. The dihedral distribution indicated towards a right-handed helical formation for TPN XIIc in both solvents. Dihedral angle based principal component analysis revealed a propensity for a slightly bent, helical folded conformation in water solvent, while two distinct conformations were reve...
A major genetic suspect for Alzheimer’s disease is the pathological conformation assumed by apoli... more A major genetic suspect for Alzheimer’s disease is the pathological conformation assumed by apolipoprotein E4 (ApoE4) through intramolecular interaction. In the present study, a large library of natural compounds was screened against ApoE4 to identify novel therapeutic molecules that can prevent ApoE4 from being converted to its pathological conformation. We report two such natural compounds PHC and IAH that bound to the active site of ApoE4 during the docking process. The binding analysis suggested that they have a strong mechanistic ability to correct the pathological structural orientation of ApoE4 by preventing repulsion between Arg 61 and Arg 112, thus inhibiting the formation of a salt bridge between Arg 61 and Glu 255. However, when the molecular dynamics simulations were carried out, structural changes in the PHC-bound complex forced PHC to move out of the cavity thus destabilizing the complex. However, IAH was structurally stable inside the binding pocket throughout the sim...
This study examined the structural diversity and bioactivity of peptaibol compounds produced by s... more This study examined the structural diversity and bioactivity of peptaibol compounds produced by species from the phylogenetically separated Longibrachiatum Clade of the filamentous fungal genus Trichoderma, which contains several biotechnologically, agriculturally and clinically important species. HPLC-ESI-MS investigations of crude extracts from 17 species of the Longibrachiatum Clade (T.
and belong to clade of , the largest and most diverse group of this genus. They produce a wide ra... more and belong to clade of , the largest and most diverse group of this genus. They produce a wide range of bioactive secondary metabolites, including peptaibols with antibacterial, antifungal, and antiviral properties. The unusual amino acid residues of peptaibols, i.e., α-aminoisobutyric acid (Aib), isovaline (Iva), and the C-terminal 1,2-amino alcohol make them unique among peptides. In this study, the peptaibiomes of and were investigated by HPLC-ESI-MS. The examined strains appeared to produce 19-residue peptaibols, most of which are unknown from literature, but their amino acid sequences are similar to those of trikoningins, tricholongins, trichostrigocins, trichorzianins, and trichorzins. A new group of peptaibols detected in are described here under the name "Koningiopsin". Trikoningin KA V, the closest peptaibol compound to the peptaibols produced by these two strains, was selected for structural investigation by short MD simulation, which revealed that many residues ...
International journal of biological macromolecules, Jan 7, 2018
Plants are endowed with an innate immune system, which enables them to protect themselves from pe... more Plants are endowed with an innate immune system, which enables them to protect themselves from pest and pathogen. The participation of pathogenesis-related (PR) proteins is one of the most crucial events of inducible plant defense response. Herein, we report the characterization of CaHaPR-4, a Helicoverpa-inducible class II PR-4 protein from chickpea. Bioinformatic analysis of CaHaPR-4 protein indicated the presence of a signal peptide, barwin domain but it lacks the chitin-binding site/hevein domain. The recombinant CaHaPR-4 is bestowed with RNase and bivalent ion-dependent DNase activity. Further, the RNA and DNA binding sites were identified and confirmed by analyzing interactions between mutated CaHaPR-4 with the altered active site and ribonuclease inhibitor, 5'ADP and DNase inhibitor, 2‑nitro‑5‑thiocyanobenzoic acid (NTCB) using 3D modeling and docking studies. Moreover, CaHaPR-4 shows antifungal activity as well as growth inhibiting properties against neonatal podborer la...
Peptaibols are short peptides of fungal origin produced by non-ribosomal peptide synthetases (NRP... more Peptaibols are short peptides of fungal origin produced by non-ribosomal peptide synthetases (NRPS) and are known to have interesting biological properties including pore formation in bilayer membranes which imparts them antibacterial, antifungal and sometimes antiviral properties. They have also been shown to elicit plant resistance mechanisms. Peptaibols are characterized by non-standard amino acid content like aminoisobutyric acid (Aib), D-isovaline, an acetylated N-terminal and a C-terminal amino-alcohol (e.g. valinol). Given the interesting and promising nature of these peptides, an optimized extraction and purification procedure along with primary structure determination by HPLC-ESI-MS was carried out in the case of the peptaibols produced by the mushroom green mould pathogens Trichoderma pleuroti and T. aggressivum f. europaeum. The three-dimensional structure of a new hypomurocin-like peptaibol detected in T. aggressivum was elucidated using 100 ns long molecular dynamics simulation based on Amber14 force fields and parameterization of non-standard amino acid residues Aib, D-isovaline and C-terminal valinol. The simulated structure shows formation of helical motifs with a break introduced by proline as expected from this class of molecules. The N- and C-terminals are the most variable regions which might have an implication in membrane binding and function. All Aib residues show an alternating left-handed and right-handed alpha helix formation throughout the trajectory owing to its achiral nature but the presence of other residues like leucine, glutamine and valine shift the whole structure towards a right-handed conformation. This study is the stepping stone for establishing a structure-activity relationship for this class of molecules which, in turn, may help in their possible exploitation as therapeutics or agricultural agents.
Uploads
Papers by Chetna Tyagi