Angewandte Chemie International Edition in English, 1980
Heterosubstituted 1,3,5‐hexatrienes undergo thermal and photochemical cyclizations, most of which... more Heterosubstituted 1,3,5‐hexatrienes undergo thermal and photochemical cyclizations, most of which can be viewed as pericyclic reactions. Numerous cyclizations of this type have been reported in the literature. This article presents a systematic account of such reactions, classified according to the number and nature of the heteroatoms.
Base pairs belonging to the cis Hoogsteen/sugar-edge (H:S) family play important structural roles... more Base pairs belonging to the cis Hoogsteen/sugar-edge (H:S) family play important structural roles in folded RNA molecules. We report results of analysis of 30 representative examples spanning 16 possible base pair combinations. The study, involving alternative classification of base pairs and triplets, provides insights into intrinsic properties of these base pairs and their possible structural and functional roles.
Page 1. Aptamer - Ligand Interactions at the Ligand Binding Site of PreQ1 Riboswitch by Preethi S... more Page 1. Aptamer - Ligand Interactions at the Ligand Binding Site of PreQ1 Riboswitch by Preethi SP, Purshotam Sharma, Abhijit Mitra in Applied Theory on Molecular Systems 2011 (ATOMS 2011) Report No: IIIT/TR/2011/-1 Centre for Computational Natural Sciences and Bioinformatics International Institute of Information Technology Hyderabad - 500 032, INDIA November 2011 Page 2. Aptamer - Ligand Interactions at the Ligand Binding Site of PreQ1 Riboswitch Preethi SP † , Purshotam Sharma, †* Abhijit Mitra † ...
Riboswitches are ligand dependent gene regulatory elements, found in mRNA transcripts. They are c... more Riboswitches are ligand dependent gene regulatory elements, found in mRNA transcripts. They are composed of two distinct domains: a 'ligand-binding'or aptamer domain and an expression platform. Communication between the two domains take place through ligand binding induced conformational changes which control downstream gene expression by turning it on or off at either the transcription and/or at the translation level. Till date, more than 20 different classes of riboswitches have been discovered and understanding their ...
Molecular level understanding of mutational effects on stability and activity of enzymes is chall... more Molecular level understanding of mutational effects on stability and activity of enzymes is challenging particularly when several point mutations are incorporated during the directed evolution experiments. In our earlier study, we have suggested the lack of consistency in the effect of point mutations incorporated during the initial generations of directed evolution experiments, towards conformational stabilization of B. subtilis lipase mutants of later generations. Here, we report that the cumulative point mutations incorporated in mutants 2M (with two point mutations) to 6M (with six point mutations) possibly do not retain their original stabilizing nature in the most thermostable 12M mutant (with 12 point mutations). We have carried out MD simulations using structures incorporating reversal of different sets of point mutations to assess their effect on the conformational stability and activity of 12M. Our analysis has revealed that reversal of certain point mutations in 12M had little effect on its conformational stability, suggesting that these mutations were probably inconsequential towards the thermostability of the 12M mutant. Interestingly these mutations involved evolutionarily conserved residues. On the other hand, some of the other point mutations incorporated in nonconserved regions, appeared to contribute significantly towards the conformational stability and/or activity of 12M. Based on the analysis of dynamics of in silico mutants generated using the consensus sequence, we identified experimentally verifiable residue positions to further increase the conformational stability and activity of the 12M mutant.
Molecular level understanding of physiochemical interactions responsible for the structure and dy... more Molecular level understanding of physiochemical interactions responsible for the structure and dynamics of functional RNA is a major challenge to the scientific community. RNA structural diversity is mainly due to the presence of non-canonical base-pairs, phosphate mediated interactions and interactions between two or more nucleotides involving water molecules and ions that stabilize folded RNA structures. BPFIND and INCAR are two complementary tools developed to analyse RNA 3D structure in terms of hydrogen-bonded secondary structural elements interacting through primarily non-canonical tertiary base pairing interactions. Identification of recurring combinations of such elements or motifs, important in terms of architecture enhances our understanding of the RNA tertiary structures. First tool, Base Pair Finder (BPFIND), detects and analyzes all canonical and non-canonical basepairs and base triples involving at least two direct hydrogen bonds formed between polar atoms of the bases...
Tools for RNA structural Informatics: BPFIND, INCAR and VASTERN Sohini Bhattacharya1, B. Ram Saga... more Tools for RNA structural Informatics: BPFIND, INCAR and VASTERN Sohini Bhattacharya1, B. Ram Sagar1,2, Dhananjay Bhattacharyya3, Gopalakrishnan Bulusu1,4 and Abhijit Mitra1 1CCNSB, International Institute of Information Technology, Gachibowli,Hyderabad-500032, India 2IBM India Pvt. Ltd., TPO B, Yerwada, Pune, India 3Biophysics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India 4Life Sciences R&D, TCS Innovation Lab Hyderabad, Madhapur, Hyderabad 500081, India Molecular level understanding of physiochemical interactions responsible for the structure and dynamics of functional RNA is a major challenge to the scientific community. RNA structural diversity is mainly due to the presence of non-canonical base-pairs, phosphate mediated interactions and interactions between two or more nucleotides involving water molecules and ions that stabilize folded RNA structures. BPFIND and INCAR are two complementary tools developed to analyse RNA 3D structure in ter...
RNA structural bioinformatics has developed, into a vibrant interdisciplinary area, in response t... more RNA structural bioinformatics has developed, into a vibrant interdisciplinary area, in response to the emergence of noncoding RNA molecules as key regulatory players in nearly all important biological processes. Here we introduce the different conceptual tools and available resources, related to this new area. We also review its application in studying the role of RNA-protein interactions.
In some bacteria, the intracellular concentration of several amino acids is controlled by riboswi... more In some bacteria, the intracellular concentration of several amino acids is controlled by riboswitches. One class of such riboswitches is Thermotoga maritima lysine-responsive riboswitch. It regulates the downstream expression of aspartate-semialdehyde dehydrogenase, which is involved in synthesis of precursor for methionine, threonine, lysine and diaminopimelate, depending on the presence or absence of small metabolite lysine. The GC-rich lysine riboswitch is among the longest and most complexly folded metabolite-sensing aptamers. Crystal structures of lysine sensing domain of riboswitch in presence and absence of lysine, feature a complex architecture, involving a modified four-way junction (J1-2, J2-3, J4-5 and J5-1) organized between coaxial bundles of three helices (P2, P3, P4) above and two helices (P1, P5) below. An intriguing structure to visualize is that adopted by P2, a long helix, which experiences two turns to have kissing-loop interactions between L2 and L3. The bindin...
Unlike structures of double stranded DNA, stabilized by canonical base pairings, single stranded ... more Unlike structures of double stranded DNA, stabilized by canonical base pairings, single stranded RNA molecules are known to fold into complex functional 3D structures. Several of these structures provide sites for binding with cognate molecules that induce conformational changes related to their respective functionalities. Their structures and functional dynamics are scripted by a multitude of noncovalent interactions, involving base edges, 2’-OH of ribose, backbone phosphates and metal cations. In the context of the importance of the ribosome as a potential drug target [1], we have studied the geometries and interaction energies associated with hydrogen bonded base pairs and pseudo pairs observed in crystal structures of drug molecules complexed with their target RNAs. Previous studies, as reviewed recently [2], provide insights into the structural aspects of these RNAligand interactions. However, the molecular level understanding of their role in RNA functions require the analysis...
ABSTRACT RNA 3D structure is currently analyzed in terms of strongly hydrogen-bonded secondary st... more ABSTRACT RNA 3D structure is currently analyzed in terms of strongly hydrogen-bonded secondary structural elements interacting through primarily noncanonical tertiary base pairing interactions. Identification of recurring combinations of such elements as motifs, important in terms of architecture or as anchors for association, enhances our understanding of the RNA tertiary structures. Current approaches in motif mining are constrained by their dependence on identification of strongly hydrogen bonded base pairs. In our work, we have attempted a bottom-up approach towards identifying and characterizing structural features responsible for the complex architecture and dynamics of functional RNA molecules. At the lower end we have studied, non-covalent interactions such as inter-nucleotide hydrogen bonding interactions, water and ion mediated interactions; and at the higher end we have tried to capture the recurrent structural motifs made of several base-pairs and higher order. To study all the important weak and 'other than base base' interactions, within a non-redundant dataset of functional RNA molecules, an in house developed python based automated tool INTER-NUCLEOTIDE CONTACT ANNOTATOR IN RNA (INCAR) is used. INCAR efficiently manages space and time complexity to capture, categorize and suitably annotate all significant inter nucleobase interactions. Results are with high specificity, without compromising on sensitivity, with respect to currently available benchmarks. Our analysis highlights the importance of backbone related interactions, importance of weak hydrogen bonds, and predominance of a specific bifurcated geometry and involvement of different pattern of higher order interactions detected by INCAR in several RNA structural motifs.
International Journal of Knowledge Discovery in Bioinformatics, 2011
Independent folding units which have the capability of carrying out biological functions have bee... more Independent folding units which have the capability of carrying out biological functions have been classified as “protein domains”. These minimal structural units lead not only to considerable sequence changes of protein domains of similar folds and functions, but also gives rise to remarkable length variations under evolutionary pressure. Rapid and heuristic sequence search algorithms are generally sensitive and effective in recognizing protein domains that are distantly related within large sequence databases, but are not well-suited to identify remote homologues of varying lengths. An even more challenging aspect is introduced to distinguish reliable hits from a vast number of putative false positives that could have suboptimal sequence similarities. Here, the authors present a data-mining approach that provides stage-specific filters in sequence searches to reliably accumulate remote homologues, which encourages sampling of length variations albeit with a low false positive rate...
Angewandte Chemie International Edition in English, 1980
Heterosubstituted 1,3,5‐hexatrienes undergo thermal and photochemical cyclizations, most of which... more Heterosubstituted 1,3,5‐hexatrienes undergo thermal and photochemical cyclizations, most of which can be viewed as pericyclic reactions. Numerous cyclizations of this type have been reported in the literature. This article presents a systematic account of such reactions, classified according to the number and nature of the heteroatoms.
Base pairs belonging to the cis Hoogsteen/sugar-edge (H:S) family play important structural roles... more Base pairs belonging to the cis Hoogsteen/sugar-edge (H:S) family play important structural roles in folded RNA molecules. We report results of analysis of 30 representative examples spanning 16 possible base pair combinations. The study, involving alternative classification of base pairs and triplets, provides insights into intrinsic properties of these base pairs and their possible structural and functional roles.
Page 1. Aptamer - Ligand Interactions at the Ligand Binding Site of PreQ1 Riboswitch by Preethi S... more Page 1. Aptamer - Ligand Interactions at the Ligand Binding Site of PreQ1 Riboswitch by Preethi SP, Purshotam Sharma, Abhijit Mitra in Applied Theory on Molecular Systems 2011 (ATOMS 2011) Report No: IIIT/TR/2011/-1 Centre for Computational Natural Sciences and Bioinformatics International Institute of Information Technology Hyderabad - 500 032, INDIA November 2011 Page 2. Aptamer - Ligand Interactions at the Ligand Binding Site of PreQ1 Riboswitch Preethi SP † , Purshotam Sharma, †* Abhijit Mitra † ...
Riboswitches are ligand dependent gene regulatory elements, found in mRNA transcripts. They are c... more Riboswitches are ligand dependent gene regulatory elements, found in mRNA transcripts. They are composed of two distinct domains: a 'ligand-binding'or aptamer domain and an expression platform. Communication between the two domains take place through ligand binding induced conformational changes which control downstream gene expression by turning it on or off at either the transcription and/or at the translation level. Till date, more than 20 different classes of riboswitches have been discovered and understanding their ...
Molecular level understanding of mutational effects on stability and activity of enzymes is chall... more Molecular level understanding of mutational effects on stability and activity of enzymes is challenging particularly when several point mutations are incorporated during the directed evolution experiments. In our earlier study, we have suggested the lack of consistency in the effect of point mutations incorporated during the initial generations of directed evolution experiments, towards conformational stabilization of B. subtilis lipase mutants of later generations. Here, we report that the cumulative point mutations incorporated in mutants 2M (with two point mutations) to 6M (with six point mutations) possibly do not retain their original stabilizing nature in the most thermostable 12M mutant (with 12 point mutations). We have carried out MD simulations using structures incorporating reversal of different sets of point mutations to assess their effect on the conformational stability and activity of 12M. Our analysis has revealed that reversal of certain point mutations in 12M had little effect on its conformational stability, suggesting that these mutations were probably inconsequential towards the thermostability of the 12M mutant. Interestingly these mutations involved evolutionarily conserved residues. On the other hand, some of the other point mutations incorporated in nonconserved regions, appeared to contribute significantly towards the conformational stability and/or activity of 12M. Based on the analysis of dynamics of in silico mutants generated using the consensus sequence, we identified experimentally verifiable residue positions to further increase the conformational stability and activity of the 12M mutant.
Molecular level understanding of physiochemical interactions responsible for the structure and dy... more Molecular level understanding of physiochemical interactions responsible for the structure and dynamics of functional RNA is a major challenge to the scientific community. RNA structural diversity is mainly due to the presence of non-canonical base-pairs, phosphate mediated interactions and interactions between two or more nucleotides involving water molecules and ions that stabilize folded RNA structures. BPFIND and INCAR are two complementary tools developed to analyse RNA 3D structure in terms of hydrogen-bonded secondary structural elements interacting through primarily non-canonical tertiary base pairing interactions. Identification of recurring combinations of such elements or motifs, important in terms of architecture enhances our understanding of the RNA tertiary structures. First tool, Base Pair Finder (BPFIND), detects and analyzes all canonical and non-canonical basepairs and base triples involving at least two direct hydrogen bonds formed between polar atoms of the bases...
Tools for RNA structural Informatics: BPFIND, INCAR and VASTERN Sohini Bhattacharya1, B. Ram Saga... more Tools for RNA structural Informatics: BPFIND, INCAR and VASTERN Sohini Bhattacharya1, B. Ram Sagar1,2, Dhananjay Bhattacharyya3, Gopalakrishnan Bulusu1,4 and Abhijit Mitra1 1CCNSB, International Institute of Information Technology, Gachibowli,Hyderabad-500032, India 2IBM India Pvt. Ltd., TPO B, Yerwada, Pune, India 3Biophysics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India 4Life Sciences R&D, TCS Innovation Lab Hyderabad, Madhapur, Hyderabad 500081, India Molecular level understanding of physiochemical interactions responsible for the structure and dynamics of functional RNA is a major challenge to the scientific community. RNA structural diversity is mainly due to the presence of non-canonical base-pairs, phosphate mediated interactions and interactions between two or more nucleotides involving water molecules and ions that stabilize folded RNA structures. BPFIND and INCAR are two complementary tools developed to analyse RNA 3D structure in ter...
RNA structural bioinformatics has developed, into a vibrant interdisciplinary area, in response t... more RNA structural bioinformatics has developed, into a vibrant interdisciplinary area, in response to the emergence of noncoding RNA molecules as key regulatory players in nearly all important biological processes. Here we introduce the different conceptual tools and available resources, related to this new area. We also review its application in studying the role of RNA-protein interactions.
In some bacteria, the intracellular concentration of several amino acids is controlled by riboswi... more In some bacteria, the intracellular concentration of several amino acids is controlled by riboswitches. One class of such riboswitches is Thermotoga maritima lysine-responsive riboswitch. It regulates the downstream expression of aspartate-semialdehyde dehydrogenase, which is involved in synthesis of precursor for methionine, threonine, lysine and diaminopimelate, depending on the presence or absence of small metabolite lysine. The GC-rich lysine riboswitch is among the longest and most complexly folded metabolite-sensing aptamers. Crystal structures of lysine sensing domain of riboswitch in presence and absence of lysine, feature a complex architecture, involving a modified four-way junction (J1-2, J2-3, J4-5 and J5-1) organized between coaxial bundles of three helices (P2, P3, P4) above and two helices (P1, P5) below. An intriguing structure to visualize is that adopted by P2, a long helix, which experiences two turns to have kissing-loop interactions between L2 and L3. The bindin...
Unlike structures of double stranded DNA, stabilized by canonical base pairings, single stranded ... more Unlike structures of double stranded DNA, stabilized by canonical base pairings, single stranded RNA molecules are known to fold into complex functional 3D structures. Several of these structures provide sites for binding with cognate molecules that induce conformational changes related to their respective functionalities. Their structures and functional dynamics are scripted by a multitude of noncovalent interactions, involving base edges, 2’-OH of ribose, backbone phosphates and metal cations. In the context of the importance of the ribosome as a potential drug target [1], we have studied the geometries and interaction energies associated with hydrogen bonded base pairs and pseudo pairs observed in crystal structures of drug molecules complexed with their target RNAs. Previous studies, as reviewed recently [2], provide insights into the structural aspects of these RNAligand interactions. However, the molecular level understanding of their role in RNA functions require the analysis...
ABSTRACT RNA 3D structure is currently analyzed in terms of strongly hydrogen-bonded secondary st... more ABSTRACT RNA 3D structure is currently analyzed in terms of strongly hydrogen-bonded secondary structural elements interacting through primarily noncanonical tertiary base pairing interactions. Identification of recurring combinations of such elements as motifs, important in terms of architecture or as anchors for association, enhances our understanding of the RNA tertiary structures. Current approaches in motif mining are constrained by their dependence on identification of strongly hydrogen bonded base pairs. In our work, we have attempted a bottom-up approach towards identifying and characterizing structural features responsible for the complex architecture and dynamics of functional RNA molecules. At the lower end we have studied, non-covalent interactions such as inter-nucleotide hydrogen bonding interactions, water and ion mediated interactions; and at the higher end we have tried to capture the recurrent structural motifs made of several base-pairs and higher order. To study all the important weak and 'other than base base' interactions, within a non-redundant dataset of functional RNA molecules, an in house developed python based automated tool INTER-NUCLEOTIDE CONTACT ANNOTATOR IN RNA (INCAR) is used. INCAR efficiently manages space and time complexity to capture, categorize and suitably annotate all significant inter nucleobase interactions. Results are with high specificity, without compromising on sensitivity, with respect to currently available benchmarks. Our analysis highlights the importance of backbone related interactions, importance of weak hydrogen bonds, and predominance of a specific bifurcated geometry and involvement of different pattern of higher order interactions detected by INCAR in several RNA structural motifs.
International Journal of Knowledge Discovery in Bioinformatics, 2011
Independent folding units which have the capability of carrying out biological functions have bee... more Independent folding units which have the capability of carrying out biological functions have been classified as “protein domains”. These minimal structural units lead not only to considerable sequence changes of protein domains of similar folds and functions, but also gives rise to remarkable length variations under evolutionary pressure. Rapid and heuristic sequence search algorithms are generally sensitive and effective in recognizing protein domains that are distantly related within large sequence databases, but are not well-suited to identify remote homologues of varying lengths. An even more challenging aspect is introduced to distinguish reliable hits from a vast number of putative false positives that could have suboptimal sequence similarities. Here, the authors present a data-mining approach that provides stage-specific filters in sequence searches to reliably accumulate remote homologues, which encourages sampling of length variations albeit with a low false positive rate...
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