Comparative structural bioinformatics analysis of Bacillus amyloliquefaciens chemotaxis proteins within Bacillus subtilis group
- Yssel, Anna, Reva, Oleg, Tastan Bishop, Özlem
- Authors: Yssel, Anna , Reva, Oleg , Tastan Bishop, Özlem
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123966 , vital:35521 , https://doi.10.1007/s00253-011-3582-y
- Description: Chemotaxis is a process in which bacteria sense their chemical environment and move towards more favorable conditions. Since plant colonization by bacteria is a multifaceted process which requires a response to the complex chemical environment, a finely tuned and sensitive chemotaxis system is needed. Members of the Bacillus subtilis group including Bacillus amyloliquefaciens are industrially important, for example, as bio-pesticides. The group exhibits plant growth-promoting characteristics, with different specificity towards certain host plants. Therefore, we hypothesize that while the principal molecular mechanisms of bacterial chemotaxis may be conserved, the bacterial chemotaxis system may need an evolutionary tweaking to adapt it to specific requirements, particularly in the process of evolution of free-living soil organisms, towards plant colonization behaviour. To date, almost nothing is known about what parts of the chemotaxis proteins are subjected to positive amino acid substitutions, involved in adjusting the chemotaxis system of bacteria during speciation. In this novel study, positively selected and purified sites of chemotaxis proteins were calculated, and these residues were mapped onto homology models that were built for the chemotaxis proteins, in an attempt to understand the spatial evolution of the chemotaxis proteins. Various positively selected amino acids were identified in semi-conserved regions of the proteins away from the known active sites.
- Full Text:
- Date Issued: 2011
- Authors: Yssel, Anna , Reva, Oleg , Tastan Bishop, Özlem
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123966 , vital:35521 , https://doi.10.1007/s00253-011-3582-y
- Description: Chemotaxis is a process in which bacteria sense their chemical environment and move towards more favorable conditions. Since plant colonization by bacteria is a multifaceted process which requires a response to the complex chemical environment, a finely tuned and sensitive chemotaxis system is needed. Members of the Bacillus subtilis group including Bacillus amyloliquefaciens are industrially important, for example, as bio-pesticides. The group exhibits plant growth-promoting characteristics, with different specificity towards certain host plants. Therefore, we hypothesize that while the principal molecular mechanisms of bacterial chemotaxis may be conserved, the bacterial chemotaxis system may need an evolutionary tweaking to adapt it to specific requirements, particularly in the process of evolution of free-living soil organisms, towards plant colonization behaviour. To date, almost nothing is known about what parts of the chemotaxis proteins are subjected to positive amino acid substitutions, involved in adjusting the chemotaxis system of bacteria during speciation. In this novel study, positively selected and purified sites of chemotaxis proteins were calculated, and these residues were mapped onto homology models that were built for the chemotaxis proteins, in an attempt to understand the spatial evolution of the chemotaxis proteins. Various positively selected amino acids were identified in semi-conserved regions of the proteins away from the known active sites.
- Full Text:
- Date Issued: 2011
Study of protein complexes via homology modeling, applied to cysteine proteases and their protein inhibitors:
- Tastan Bishop, Özlem, Kroon, Matthys
- Authors: Tastan Bishop, Özlem , Kroon, Matthys
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148070 , vital:38707 , DOI: 10.1007/s00894-011-0990-y
- Description: This paper develops and evaluates large-scale calculation of 3D structures of protein complexes by homology modeling as a promising new approach for protein docking. The complexes investigated were papain-like cysteine proteases and their protein inhibitors, which play numerous roles in human and parasitic metabolisms. The structural modeling was performed in two parts. For the first part (evaluation set), nine crystal structure complexes were selected, 1325 homology models of known complexes were rebuilt by various templates including hybrids, allowing an analysis of the factors influencing the accuracy of the models. The important considerations for modeling the interface were protease coverage and inhibitor sequence identity. In the second part (study set), the findings of the evaluation set were used to select appropriate templates to model novel cysteine protease-inhibitor complexes from human and malaria parasites Plasmodium falciparum and Plasmodium vivax. The energy scores, considering the evaluation set, indicate that the models are of high accuracy.
- Full Text:
- Date Issued: 2011
- Authors: Tastan Bishop, Özlem , Kroon, Matthys
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148070 , vital:38707 , DOI: 10.1007/s00894-011-0990-y
- Description: This paper develops and evaluates large-scale calculation of 3D structures of protein complexes by homology modeling as a promising new approach for protein docking. The complexes investigated were papain-like cysteine proteases and their protein inhibitors, which play numerous roles in human and parasitic metabolisms. The structural modeling was performed in two parts. For the first part (evaluation set), nine crystal structure complexes were selected, 1325 homology models of known complexes were rebuilt by various templates including hybrids, allowing an analysis of the factors influencing the accuracy of the models. The important considerations for modeling the interface were protease coverage and inhibitor sequence identity. In the second part (study set), the findings of the evaluation set were used to select appropriate templates to model novel cysteine protease-inhibitor complexes from human and malaria parasites Plasmodium falciparum and Plasmodium vivax. The energy scores, considering the evaluation set, indicate that the models are of high accuracy.
- Full Text:
- Date Issued: 2011
The PINIT domain of PIAS3: structure-function analysis of its interaction with STAT3
- Mautsa, Nicodemus, Prinsloo, Earl, Tastan Bishop, Özlem, Blatch, Gregory L
- Authors: Mautsa, Nicodemus , Prinsloo, Earl , Tastan Bishop, Özlem , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148082 , vital:38708 , DOI: 10.1002/jmr.1111
- Description: The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3) regulates the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) which regulates transcription of genes involved in cell growth, proliferation and apoptosis. The conserved proline, isoleucine, asparagine, isoleucine, threonine (PINIT) domain of PIAS3 is thought to promote STAT3–PIAS3 interaction.
- Full Text:
- Date Issued: 2011
- Authors: Mautsa, Nicodemus , Prinsloo, Earl , Tastan Bishop, Özlem , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148082 , vital:38708 , DOI: 10.1002/jmr.1111
- Description: The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3) regulates the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) which regulates transcription of genes involved in cell growth, proliferation and apoptosis. The conserved proline, isoleucine, asparagine, isoleucine, threonine (PINIT) domain of PIAS3 is thought to promote STAT3–PIAS3 interaction.
- Full Text:
- Date Issued: 2011
Analysis of protein thermostability enhancing factors in industrially important thermus bacteria species
- Kumwenda, Benjamin, Litthauer, Derek, Tastan Bishop, Özlem, Reva, Oleg
- Authors: Kumwenda, Benjamin , Litthauer, Derek , Tastan Bishop, Özlem , Reva, Oleg
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123085 , vital:35404 , https://doi.10.4137/EBO.S12539
- Description: Elucidation of evolutionary factors that enhance protein thermostability is a critical problem and was the focus of this work on Thermus species. Pairs of orthologous sequences of T. scotoductus SA-01 and T. thermophilus HB27, with the largest negative minimum folding energy (MFE) as predicted by the UNAFold algorithm, were statistically analyzed. Favored substitutions of amino acids residues and their properties were determined. Substitutions were analyzed in modeled protein structures to determine their locations and contribution to energy differences using PyMOL and FoldX programs respectively. Dominant trends in amino acid substitutions consistent with differences in thermostability between orthologous sequences were observed. T. thermophilus thermophilic proteins showed an increase in non-polar, tiny, and charged amino acids. An abundance of alanine substituted by serine and threonine, as well as arginine substituted by glutamine and lysine was observed in T. thermophilus HB27. Structural comparison showed that stabilizing mutations occurred on surfaces and loops in protein structures.
- Full Text:
- Date Issued: 2013
- Authors: Kumwenda, Benjamin , Litthauer, Derek , Tastan Bishop, Özlem , Reva, Oleg
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123085 , vital:35404 , https://doi.10.4137/EBO.S12539
- Description: Elucidation of evolutionary factors that enhance protein thermostability is a critical problem and was the focus of this work on Thermus species. Pairs of orthologous sequences of T. scotoductus SA-01 and T. thermophilus HB27, with the largest negative minimum folding energy (MFE) as predicted by the UNAFold algorithm, were statistically analyzed. Favored substitutions of amino acids residues and their properties were determined. Substitutions were analyzed in modeled protein structures to determine their locations and contribution to energy differences using PyMOL and FoldX programs respectively. Dominant trends in amino acid substitutions consistent with differences in thermostability between orthologous sequences were observed. T. thermophilus thermophilic proteins showed an increase in non-polar, tiny, and charged amino acids. An abundance of alanine substituted by serine and threonine, as well as arginine substituted by glutamine and lysine was observed in T. thermophilus HB27. Structural comparison showed that stabilizing mutations occurred on surfaces and loops in protein structures.
- Full Text:
- Date Issued: 2013
Plasmodium falciparum Hsp70-x : a heat shock protein at the host-parasite interface
- Hatherley, Rowan, Blatch, Gregory L, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Blatch, Gregory L , Tastan Bishop, Özlem
- Date: 2013
- Language: English
- Type: Article
- Identifier: vital:6489 , http://hdl.handle.net/10962/d1007081 , https://dx.doi.org/10.1080/07391102.2013.834849
- Description: Plasmodium falciparum 70 kDa heat shock proteins (PfHsp70s) are expressed at all stages of the pathogenic erythrocytic phase of the malaria parasite lifecycle. There are six PfHsp70s,all of which have orthologues in other plasmodial species, except for PfHsp70-x which is unique to P. falciparum. This paper highlights a number of original results obtained by a detailed bioinformatics analysis of the protein. Large scale sequence analysis indicated the presence of an extended transit peptide sequence of PfHsp70-x which potentially directs it to the endoplasmic reticulum (ER). Further analysis showed that PfHsp70-x does not have an ER-retention sequence, suggesting that the protein transits through the ER and is secreted into the parasitophorous vacuole (PV) or beyond into the erythrocyte cytosol. These results are consistent with experimental findings. Next, possible interactions between PfHsp70-x and exported P. falciparum Hsp40s or host erythrocyte DnaJs were interrogated by modeling and docking. Docking results indicated that interaction between PfHsp70-x and each of the Hsp40s, regardless of biological feasibility, seems equally likely. This suggests that J domain might not provide the specificity in the formation of unique Hsp70-Hsp40 complexes, but that the specificity might be provided by other domains of Hsp40s. By studying different structural conformations of PfHsp70-x, it was shown that Hsp40s can only bind when PfHsp70-x is in a certain conformation. Additionally, this work highlighted the possible dependence of the substrate binding domain residues on the orientation of the α-helical lid for formation of the substrate binding pocket.
- Full Text:
- Date Issued: 2013
- Authors: Hatherley, Rowan , Blatch, Gregory L , Tastan Bishop, Özlem
- Date: 2013
- Language: English
- Type: Article
- Identifier: vital:6489 , http://hdl.handle.net/10962/d1007081 , https://dx.doi.org/10.1080/07391102.2013.834849
- Description: Plasmodium falciparum 70 kDa heat shock proteins (PfHsp70s) are expressed at all stages of the pathogenic erythrocytic phase of the malaria parasite lifecycle. There are six PfHsp70s,all of which have orthologues in other plasmodial species, except for PfHsp70-x which is unique to P. falciparum. This paper highlights a number of original results obtained by a detailed bioinformatics analysis of the protein. Large scale sequence analysis indicated the presence of an extended transit peptide sequence of PfHsp70-x which potentially directs it to the endoplasmic reticulum (ER). Further analysis showed that PfHsp70-x does not have an ER-retention sequence, suggesting that the protein transits through the ER and is secreted into the parasitophorous vacuole (PV) or beyond into the erythrocyte cytosol. These results are consistent with experimental findings. Next, possible interactions between PfHsp70-x and exported P. falciparum Hsp40s or host erythrocyte DnaJs were interrogated by modeling and docking. Docking results indicated that interaction between PfHsp70-x and each of the Hsp40s, regardless of biological feasibility, seems equally likely. This suggests that J domain might not provide the specificity in the formation of unique Hsp70-Hsp40 complexes, but that the specificity might be provided by other domains of Hsp40s. By studying different structural conformations of PfHsp70-x, it was shown that Hsp40s can only bind when PfHsp70-x is in a certain conformation. Additionally, this work highlighted the possible dependence of the substrate binding domain residues on the orientation of the α-helical lid for formation of the substrate binding pocket.
- Full Text:
- Date Issued: 2013
Bioinformatics and data analysis in microbiology:
- Authors: Tastan Bishop, Özlem
- Date: 2014
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/148104 , vital:38710 , ISBN 9781908230737 , https://books.google.co.za/books?id=-G07DwAAQBAJanddq=Bioinformatics+and+data+analysis+in+microbiologyandsource=gbs_navlinks_s
- Description: The rapid advancement of sequencing techniques, coupled with the new methodologies of bioinformatics to handle large-scale data analysis, are providing exciting opportunities for us to understand microbial communities from a variety of environments beyond previous imagination. This book provides invaluable, up-to-date and detailed information on various aspects of bioinformatics data analysis with applications to microbiology. It describes a number of different useful bioinformatics tools, makes links to some wet-lab techniques, explains different approaches to tackle a problem, talks about current challenges and limitations, gives examples of applications of bioinformatics methods to microbiology, and discusses future trends. The chapters include topics such as genome sequencing techniques, assembly, SNP analysis, annotation, comparative genomics, microbial community profiling, metagenomics, phylogenetic microarrays, barcoding and more. Each chapter is written by scientists who are expert in the field, and is peer-reviewed. Bioinformatics and Data Analysis in Microbiology is an essential book for researchers, lecturers and students involved in microbiology, bioinformatics and genome analysis.
- Full Text:
- Date Issued: 2014
- Authors: Tastan Bishop, Özlem
- Date: 2014
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/148104 , vital:38710 , ISBN 9781908230737 , https://books.google.co.za/books?id=-G07DwAAQBAJanddq=Bioinformatics+and+data+analysis+in+microbiologyandsource=gbs_navlinks_s
- Description: The rapid advancement of sequencing techniques, coupled with the new methodologies of bioinformatics to handle large-scale data analysis, are providing exciting opportunities for us to understand microbial communities from a variety of environments beyond previous imagination. This book provides invaluable, up-to-date and detailed information on various aspects of bioinformatics data analysis with applications to microbiology. It describes a number of different useful bioinformatics tools, makes links to some wet-lab techniques, explains different approaches to tackle a problem, talks about current challenges and limitations, gives examples of applications of bioinformatics methods to microbiology, and discusses future trends. The chapters include topics such as genome sequencing techniques, assembly, SNP analysis, annotation, comparative genomics, microbial community profiling, metagenomics, phylogenetic microarrays, barcoding and more. Each chapter is written by scientists who are expert in the field, and is peer-reviewed. Bioinformatics and Data Analysis in Microbiology is an essential book for researchers, lecturers and students involved in microbiology, bioinformatics and genome analysis.
- Full Text:
- Date Issued: 2014
Bioinformatics education—perspectives and challenges out of Africa
- Tastan Bishop, Özlem, Adebiyi, Ezekiel F, Alzohairy, Ahmed M, Everett, Dean B, Ghedira, Kais, Ghouila, Amel, Kumuthini, Judit, Mulder, Nicola J, Panji, Sumir, Patterton, Hugh-G
- Authors: Tastan Bishop, Özlem , Adebiyi, Ezekiel F , Alzohairy, Ahmed M , Everett, Dean B , Ghedira, Kais , Ghouila, Amel , Kumuthini, Judit , Mulder, Nicola J , Panji, Sumir , Patterton, Hugh-G
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123244 , vital:35420 , https://doi.10.1093/bib/bbu022
- Description: The discipline of bioinformatics has developed rapidly since the complete sequencing of the first genomes in the 1990s.The development of many high-throughput techniques during the last decades has ensured that bioinformatics has grown into a discipline that overlaps with, and is required for, the modern practice of virtually every field in the life sciences. This has placed a scientific premium on the availability of skilled bioinformaticians, a qualification that is extremely scarce on the African continent. The reasons for this are numerous, although the absence of a skilled bioinformatician at academic institutions to initiate a training process and build sustained capacity seems to be a common African shortcoming.This dearth of bioinformatics expertise has had a knock-on effect on the establishment of many modern high-throughput projects at African institutes, including the comprehensive and systematic analysis of genomes from African populations, which are among the most genetically diverse anywhere on the planet. Recent funding initiatives from the National Institutes of Health and theWellcomeTrust are aimed at ameliorating this shortcoming. In this paper, we discuss the problems that have limited the establishment of the bioinformatics field in Africa, as well as propose specific actions that will help with the education and training of bioinformaticians on the continent. This is an absolute requirement in anticipation of a boom in high-throughput approaches to human health issues unique to data from African populations.
- Full Text:
- Date Issued: 2014
- Authors: Tastan Bishop, Özlem , Adebiyi, Ezekiel F , Alzohairy, Ahmed M , Everett, Dean B , Ghedira, Kais , Ghouila, Amel , Kumuthini, Judit , Mulder, Nicola J , Panji, Sumir , Patterton, Hugh-G
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123244 , vital:35420 , https://doi.10.1093/bib/bbu022
- Description: The discipline of bioinformatics has developed rapidly since the complete sequencing of the first genomes in the 1990s.The development of many high-throughput techniques during the last decades has ensured that bioinformatics has grown into a discipline that overlaps with, and is required for, the modern practice of virtually every field in the life sciences. This has placed a scientific premium on the availability of skilled bioinformaticians, a qualification that is extremely scarce on the African continent. The reasons for this are numerous, although the absence of a skilled bioinformatician at academic institutions to initiate a training process and build sustained capacity seems to be a common African shortcoming.This dearth of bioinformatics expertise has had a knock-on effect on the establishment of many modern high-throughput projects at African institutes, including the comprehensive and systematic analysis of genomes from African populations, which are among the most genetically diverse anywhere on the planet. Recent funding initiatives from the National Institutes of Health and theWellcomeTrust are aimed at ameliorating this shortcoming. In this paper, we discuss the problems that have limited the establishment of the bioinformatics field in Africa, as well as propose specific actions that will help with the education and training of bioinformaticians on the continent. This is an absolute requirement in anticipation of a boom in high-throughput approaches to human health issues unique to data from African populations.
- Full Text:
- Date Issued: 2014
How to establish a bioinformatics postgraduate degree programme—a case study from South Africa
- Machanick, Philip, Tastan Bishop, Özlem
- Authors: Machanick, Philip , Tastan Bishop, Özlem
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124641 , vital:35641 , https://doi.10.1093/bib/bbu014
- Description: The Research Unit in Bioinformatics at Rhodes University (RUBi), South Africa, offers a Masters of Science in Bioinformatics.Growing demand for bioinformatics qualifications results in applications from across Africa.Courses aim to bridge gaps in the diverse backgrounds of students who range from biologists with no prior computing exposure to computer scientists with no biology background. The programme is evenly split between coursework and research, with diverse modules from a range of departments coveringmathematics, statistics, computer science and biology, with emphasis on application to bioinformatics research. The early focus on research helps bring students up to speed with working as a researcher. We measure success of the programme by the high rate of subsequent entry to PhD study: 10 of 14 students who completed in the years 2011-2013.
- Full Text:
- Date Issued: 2014
- Authors: Machanick, Philip , Tastan Bishop, Özlem
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124641 , vital:35641 , https://doi.10.1093/bib/bbu014
- Description: The Research Unit in Bioinformatics at Rhodes University (RUBi), South Africa, offers a Masters of Science in Bioinformatics.Growing demand for bioinformatics qualifications results in applications from across Africa.Courses aim to bridge gaps in the diverse backgrounds of students who range from biologists with no prior computing exposure to computer scientists with no biology background. The programme is evenly split between coursework and research, with diverse modules from a range of departments coveringmathematics, statistics, computer science and biology, with emphasis on application to bioinformatics research. The early focus on research helps bring students up to speed with working as a researcher. We measure success of the programme by the high rate of subsequent entry to PhD study: 10 of 14 students who completed in the years 2011-2013.
- Full Text:
- Date Issued: 2014
Sequence and domain conservation of the coelacanth Hsp40 and Hsp90 chaperones suggests conservation of function
- Tastan Bishop, Özlem, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Tastan Bishop, Özlem , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/126932 , vital:35936 , https://doi.10.1002/jez.b.22541
- Description: Molecular chaperones and their associated co‐chaperones play an important role in preserving and regulating the active conformational state of cellular proteins. The chaperone complement of the Indonesian Coelacanth, Latimeria menadoensis, was elucidated using transcriptomic sequences. Heat shock protein 90 (Hsp90) and heat shock protein 40 (Hsp40) chaperones, and associated cochaperones were focused on, and homologous human sequences were used to search the sequence databases. Coelacanth homologs of the cytosolic, mitochondrial and endoplasmic reticulum (ER) homologs of human Hsp90 were identified, as well as all of the major co‐chaperones of the cytosolic isoform. Most of the human Hsp40s were found to have coelacanth homologs, and the data suggested that all of the chaperone machinery for protein folding at the ribosome, protein translocation to cellular compartments such as the ER and protein degradation were conserved. Some interesting similarities and differences were identified when interrogating human, mouse, and zebrafish homologs. For example, DnaJB13 is predicted to be a non‐functional Hsp40 in humans, mouse, and zebrafish due to a corrupted histidine‐proline‐aspartic acid (HPD) motif, while the coelacanth homolog has an intact HPD. These and other comparisons enabled important functional and evolutionary questions to be posed for future experimental studies.
- Full Text:
- Date Issued: 2014
- Authors: Tastan Bishop, Özlem , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/126932 , vital:35936 , https://doi.10.1002/jez.b.22541
- Description: Molecular chaperones and their associated co‐chaperones play an important role in preserving and regulating the active conformational state of cellular proteins. The chaperone complement of the Indonesian Coelacanth, Latimeria menadoensis, was elucidated using transcriptomic sequences. Heat shock protein 90 (Hsp90) and heat shock protein 40 (Hsp40) chaperones, and associated cochaperones were focused on, and homologous human sequences were used to search the sequence databases. Coelacanth homologs of the cytosolic, mitochondrial and endoplasmic reticulum (ER) homologs of human Hsp90 were identified, as well as all of the major co‐chaperones of the cytosolic isoform. Most of the human Hsp40s were found to have coelacanth homologs, and the data suggested that all of the chaperone machinery for protein folding at the ribosome, protein translocation to cellular compartments such as the ER and protein degradation were conserved. Some interesting similarities and differences were identified when interrogating human, mouse, and zebrafish homologs. For example, DnaJB13 is predicted to be a non‐functional Hsp40 in humans, mouse, and zebrafish due to a corrupted histidine‐proline‐aspartic acid (HPD) motif, while the coelacanth homolog has an intact HPD. These and other comparisons enabled important functional and evolutionary questions to be posed for future experimental studies.
- Full Text:
- Date Issued: 2014
Human, vector and parasite Hsp90 proteins: a comparative bioinformatics analysis
- Faya, Ngonidzashe, Penkler, David L, Tastan Bishop, Özlem
- Authors: Faya, Ngonidzashe , Penkler, David L , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148038 , vital:38704 , DOI: 10.1016/j.fob.2015.11.003
- Description: The treatment of protozoan parasitic diseases is challenging, and thus identification and analysis of new drug targets is important. Parasites survive within host organisms, and some need intermediate hosts to complete their life cycle. Changing host environment puts stress on parasites, and often adaptation is accompanied by the expression of large amounts of heat shock proteins (Hsps). Among Hsps, Hsp90 proteins play an important role in stress environments. Yet, there has been little computational research on Hsp90 proteins to analyze them comparatively as potential parasitic drug targets. Here, an attempt was made to gain detailed insights into the differences between host, vector and parasitic Hsp90 proteins by large-scale bioinformatics analysis.
- Full Text:
- Date Issued: 2015
- Authors: Faya, Ngonidzashe , Penkler, David L , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148038 , vital:38704 , DOI: 10.1016/j.fob.2015.11.003
- Description: The treatment of protozoan parasitic diseases is challenging, and thus identification and analysis of new drug targets is important. Parasites survive within host organisms, and some need intermediate hosts to complete their life cycle. Changing host environment puts stress on parasites, and often adaptation is accompanied by the expression of large amounts of heat shock proteins (Hsps). Among Hsps, Hsp90 proteins play an important role in stress environments. Yet, there has been little computational research on Hsp90 proteins to analyze them comparatively as potential parasitic drug targets. Here, an attempt was made to gain detailed insights into the differences between host, vector and parasitic Hsp90 proteins by large-scale bioinformatics analysis.
- Full Text:
- Date Issued: 2015
JMS: a workflow management system and web-based cluster front-end for the Torque resource manager
- Brown, David K, Musyoka, Thommas M, Penkler, David L, Tastan Bishop, Özlem
- Authors: Brown, David K , Musyoka, Thommas M , Penkler, David L , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148049 , vital:38705 , https://arxiv.org/abs/1501.06907
- Description: Complex computational pipelines are becoming a staple of modern scientific research. Often these pipelines are resource intensive and require days of computing time. In such cases, it makes sense to run them over distributed computer clusters where they can take advantage of the aggregated resources of many powerful computers. In addition to this, researchers often want to integrate their workflows into their own web servers. In these cases, software is needed to manage the submission of jobs from the web interface to the cluster and then return the results once the job has finished executing.
- Full Text:
- Date Issued: 2015
- Authors: Brown, David K , Musyoka, Thommas M , Penkler, David L , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148049 , vital:38705 , https://arxiv.org/abs/1501.06907
- Description: Complex computational pipelines are becoming a staple of modern scientific research. Often these pipelines are resource intensive and require days of computing time. In such cases, it makes sense to run them over distributed computer clusters where they can take advantage of the aggregated resources of many powerful computers. In addition to this, researchers often want to integrate their workflows into their own web servers. In these cases, software is needed to manage the submission of jobs from the web interface to the cluster and then return the results once the job has finished executing.
- Full Text:
- Date Issued: 2015
JMS: an open source workflow management system and web-based cluster front-end for high performance computing
- Brown, David K, Penkler, David L, Musyoka, Thommas M, Tastan Bishop, Özlem
- Authors: Brown, David K , Penkler, David L , Musyoka, Thommas M , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162880 , vital:40993 , doi:10.1371/journal.pone.0134273
- Description: Complex computational pipelines are becoming a staple of modern scientific research. Often these pipelines are resource intensive and require days of computing time. In such cases, it makes sense to run them over high performance computing (HPC) clusters where they can take advantage of the aggregated resources of many powerful computers. In addition to this, researchers often want to integrate their workflows into their own web servers. In these cases, software is needed to manage the submission of jobs from the web interface to the cluster and then return the results once the job has finished executing. We have developed the Job Management System (JMS), a workflow management system and web interface for high performance computing (HPC). JMS provides users with a user-friendly web interface for creating complex workflows with multiple stages. It integrates this workflow functionality with the resource manager, a tool that is used to control and manage batch jobs on HPC clusters. As such, JMS combines workflow management functionality with cluster administration functionality.
- Full Text:
- Date Issued: 2015
- Authors: Brown, David K , Penkler, David L , Musyoka, Thommas M , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162880 , vital:40993 , doi:10.1371/journal.pone.0134273
- Description: Complex computational pipelines are becoming a staple of modern scientific research. Often these pipelines are resource intensive and require days of computing time. In such cases, it makes sense to run them over high performance computing (HPC) clusters where they can take advantage of the aggregated resources of many powerful computers. In addition to this, researchers often want to integrate their workflows into their own web servers. In these cases, software is needed to manage the submission of jobs from the web interface to the cluster and then return the results once the job has finished executing. We have developed the Job Management System (JMS), a workflow management system and web interface for high performance computing (HPC). JMS provides users with a user-friendly web interface for creating complex workflows with multiple stages. It integrates this workflow functionality with the resource manager, a tool that is used to control and manage batch jobs on HPC clusters. As such, JMS combines workflow management functionality with cluster administration functionality.
- Full Text:
- Date Issued: 2015
Plasmodium falciparum Hop: detailed analysis on complex formation with Hsp70 and Hsp90
- Hatherley, Rowan, Clitheroe, Crystal-Leigh, Faya, Ngonidzashe, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Clitheroe, Crystal-Leigh , Faya, Ngonidzashe , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125708 , vital:35810 , https://doi.10.1016/j.bbrc.2014.11.103
- Description: The heat shock organizing protein (Hop) is important in modulating the activity and co-interaction of two chaperones: heat shock protein 70 and 90 (Hsp70 and Hsp90). Recent research suggested that Plasmodium falciparum Hop (PfHop), PfHsp70 and PfHsp90 form a complex in the trophozoite infective stage. However, there has been little computational research on the malarial Hop protein in complex with other malarial Hsps. Using in silico characterization of the protein, this work showed that individual domains of Hop are evolving at different rates within the protein. Differences between human Hop (HsHop) and PfHop were identified by motif analysis. Homology modeling of PfHop and HsHop in complex with their own cytosolic Hsp90 and Hsp70 C-terminal peptide partners indicated excellent conservation of the Hop concave TPR sites bound to the C-terminal motifs of partner proteins. Further, we analyzed additional binding sites between Hop and Hsp90, and showed, for the first time, that they are distinctly less conserved between human and malaria parasite. These sites are located on the convex surface of Hop TPR2, and involved in interactions with the Hsp90 middle domain. Since the convex sites are less conserved than the concave sites, it makes their potential for malarial inhibitor design extremely attractive (as opposed to the concave sites which have been the focus of previous efforts).
- Full Text:
- Date Issued: 2015
- Authors: Hatherley, Rowan , Clitheroe, Crystal-Leigh , Faya, Ngonidzashe , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125708 , vital:35810 , https://doi.10.1016/j.bbrc.2014.11.103
- Description: The heat shock organizing protein (Hop) is important in modulating the activity and co-interaction of two chaperones: heat shock protein 70 and 90 (Hsp70 and Hsp90). Recent research suggested that Plasmodium falciparum Hop (PfHop), PfHsp70 and PfHsp90 form a complex in the trophozoite infective stage. However, there has been little computational research on the malarial Hop protein in complex with other malarial Hsps. Using in silico characterization of the protein, this work showed that individual domains of Hop are evolving at different rates within the protein. Differences between human Hop (HsHop) and PfHop were identified by motif analysis. Homology modeling of PfHop and HsHop in complex with their own cytosolic Hsp90 and Hsp70 C-terminal peptide partners indicated excellent conservation of the Hop concave TPR sites bound to the C-terminal motifs of partner proteins. Further, we analyzed additional binding sites between Hop and Hsp90, and showed, for the first time, that they are distinctly less conserved between human and malaria parasite. These sites are located on the convex surface of Hop TPR2, and involved in interactions with the Hsp90 middle domain. Since the convex sites are less conserved than the concave sites, it makes their potential for malarial inhibitor design extremely attractive (as opposed to the concave sites which have been the focus of previous efforts).
- Full Text:
- Date Issued: 2015
SANCDB: a South African natural compound database
- Hatherley, Rowan, Brown, David K, Musyoka, Thommas M, Penkler, David L, Faya, Ngonidzashe, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148337 , vital:38730 , DOI: 10.1186/s13321-015-0080-8
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148337 , vital:38730 , DOI: 10.1186/s13321-015-0080-8
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
Analysis of non-peptidic compounds as potential malarial inhibitors against plasmodial cysteine proteases via integrated virtual screening workflow
- Musyoka, Thommas M, Kanzi, Aquillah M, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123074 , vital:35403 , https://doi.10.1080/07391102.2015.1108231
- Description: Malaria is an infectious disease caused by a diverse group of erythrocytic protozoan parasites of the genus Plasmodium. It remains an exigent public health problem in the tropical areas of Africa, South America and parts of Asia and continues to take its toll in morbidity and mortality with half of the world’s population under a permanent risk of infection leading to more than half a million deaths annually (WHO, 2013). Five Plasmodium species, namely P. falciparum (Pf ), P. vivax (Pv), P. ovale (Po), P. malariae (Pm) and P. knowlesi (Pk), are known to infect humans with Pf responsible for more than 90% of the malarial fatalities reported in sub-Saharan Africa. The predominance of Pf is attributed to its adaptability (Ashley, McGready, Proux, & Nosten, 2006; Prugnolle et al., 2011). Although the high occurrence of the Duffy negative trait among African populations lowers the threat posed by Pv, it is the most frequent and widely causative agent of benign tertian malaria in other parts of the world (Mendis, Sina, Marchesini, & Carter, 2001). In addition to the listed human malarial parasite forms, several other Plasmodium species, which infect non-human laboratory models, have been identified and are of significant importance in understanding the parasite biology, the host–parasite interactions and in the drug development process (Langhorne et al., 2011).
- Full Text:
- Date Issued: 2016
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123074 , vital:35403 , https://doi.10.1080/07391102.2015.1108231
- Description: Malaria is an infectious disease caused by a diverse group of erythrocytic protozoan parasites of the genus Plasmodium. It remains an exigent public health problem in the tropical areas of Africa, South America and parts of Asia and continues to take its toll in morbidity and mortality with half of the world’s population under a permanent risk of infection leading to more than half a million deaths annually (WHO, 2013). Five Plasmodium species, namely P. falciparum (Pf ), P. vivax (Pv), P. ovale (Po), P. malariae (Pm) and P. knowlesi (Pk), are known to infect humans with Pf responsible for more than 90% of the malarial fatalities reported in sub-Saharan Africa. The predominance of Pf is attributed to its adaptability (Ashley, McGready, Proux, & Nosten, 2006; Prugnolle et al., 2011). Although the high occurrence of the Duffy negative trait among African populations lowers the threat posed by Pv, it is the most frequent and widely causative agent of benign tertian malaria in other parts of the world (Mendis, Sina, Marchesini, & Carter, 2001). In addition to the listed human malarial parasite forms, several other Plasmodium species, which infect non-human laboratory models, have been identified and are of significant importance in understanding the parasite biology, the host–parasite interactions and in the drug development process (Langhorne et al., 2011).
- Full Text:
- Date Issued: 2016
Bioinformatic characterization of type-specific sequence and structural features in auxiliary activity family 9 proteins:
- Moses, Vuyani, Hatherley, Rowan, Tastan Bishop, Özlem
- Authors: Moses, Vuyani , Hatherley, Rowan , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148358 , vital:38732 , DOI: 10.1186/s13068-016-0655-2
- Description: Due to the impending depletion of fossil fuels, it has become important to identify alternative energy sources. The biofuel industry has proven to be a promising alternative. However, owing to the complex nature of plant biomass, hence the degradation, biofuel production remains a challenge. The copper-dependent Auxiliary Activity family 9 (AA9) proteins have been found to act synergistically with other cellulose-degrading enzymes resulting in an increased rate of cellulose breakdown. AA9 proteins are lytic polysaccharide monooxygenase (LPMO) enzymes, otherwise known as polysaccharide monooxygenases (PMOs). They are further classified as Type 1, 2 or 3 PMOs, depending on the different cleavage products formed. As AA9 proteins are known to exhibit low sequence conservation, the analysis of unique features of AA9 domains of these enzymes should provide insights for the better understanding of how different AA9 PMO types function.
- Full Text:
- Date Issued: 2016
- Authors: Moses, Vuyani , Hatherley, Rowan , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148358 , vital:38732 , DOI: 10.1186/s13068-016-0655-2
- Description: Due to the impending depletion of fossil fuels, it has become important to identify alternative energy sources. The biofuel industry has proven to be a promising alternative. However, owing to the complex nature of plant biomass, hence the degradation, biofuel production remains a challenge. The copper-dependent Auxiliary Activity family 9 (AA9) proteins have been found to act synergistically with other cellulose-degrading enzymes resulting in an increased rate of cellulose breakdown. AA9 proteins are lytic polysaccharide monooxygenase (LPMO) enzymes, otherwise known as polysaccharide monooxygenases (PMOs). They are further classified as Type 1, 2 or 3 PMOs, depending on the different cleavage products formed. As AA9 proteins are known to exhibit low sequence conservation, the analysis of unique features of AA9 domains of these enzymes should provide insights for the better understanding of how different AA9 PMO types function.
- Full Text:
- Date Issued: 2016
Structure based docking and molecular dynamic studies of plasmodial cysteine proteases against a South African natural compound and its analogs:
- Musyoka, Thommas M, Kanzi, Aquillah M, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148027 , vital:38703 , DOI: 10.1038/srep23690
- Description: Identification of potential drug targets as well as development of novel antimalarial chemotherapies with unique mode of actions due to drug resistance by Plasmodium parasites are inevitable. Falcipains (falcipain-2 and falcipain-3) of Plasmodium falciparum, which catalyse the haemoglobin degradation process, are validated drug targets. Previous attempts to develop peptide based drugs against these enzymes have been futile due to the poor pharmacological profiles and susceptibility to degradation by host enzymes. This study aimed to identify potential non-peptide inhibitors against falcipains and their homologs from other Plasmodium species.
- Full Text:
- Date Issued: 2016
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148027 , vital:38703 , DOI: 10.1038/srep23690
- Description: Identification of potential drug targets as well as development of novel antimalarial chemotherapies with unique mode of actions due to drug resistance by Plasmodium parasites are inevitable. Falcipains (falcipain-2 and falcipain-3) of Plasmodium falciparum, which catalyse the haemoglobin degradation process, are validated drug targets. Previous attempts to develop peptide based drugs against these enzymes have been futile due to the poor pharmacological profiles and susceptibility to degradation by host enzymes. This study aimed to identify potential non-peptide inhibitors against falcipains and their homologs from other Plasmodium species.
- Full Text:
- Date Issued: 2016
Subcellular localisation of Theiler's murine encephalomyelitis virus (TMEV) capsid subunit VP1 vis-á-vis host protein Hsp90:
- Ross, Caroline J, Upfold, Nicole, Luke, Garry A, Tastan Bishop, Özlem, Knox, Caroline M
- Authors: Ross, Caroline J , Upfold, Nicole , Luke, Garry A , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148016 , vital:38702 , DOI: 10.1016/j.virusres.2016.06.003
- Description: The VP1 subunit of the picornavirus capsid is the major antigenic determinant and mediates host cell attachment and virus entry. To investigate the localisation of Theiler's murine encephalomyelitis virus (TMEV) VP1 during infection, a bioinformatics approach was used to predict a surface-exposed, linear epitope region of the protein for subsequent expression and purification. This region, comprising the N-terminal 112 amino acids of the protein, was then used for rabbit immunisation, and the resultant polyclonal antibodies were able to recognise full length VP1 in infected cell lysates by Western blot. Following optimisation, the antibodies were used to investigate the localisation of VP1 in relation to Hsp90 in infected cells by indirect immunofluorescence and confocal microscopy.
- Full Text:
- Date Issued: 2016
- Authors: Ross, Caroline J , Upfold, Nicole , Luke, Garry A , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148016 , vital:38702 , DOI: 10.1016/j.virusres.2016.06.003
- Description: The VP1 subunit of the picornavirus capsid is the major antigenic determinant and mediates host cell attachment and virus entry. To investigate the localisation of Theiler's murine encephalomyelitis virus (TMEV) VP1 during infection, a bioinformatics approach was used to predict a surface-exposed, linear epitope region of the protein for subsequent expression and purification. This region, comprising the N-terminal 112 amino acids of the protein, was then used for rabbit immunisation, and the resultant polyclonal antibodies were able to recognise full length VP1 in infected cell lysates by Western blot. Following optimisation, the antibodies were used to investigate the localisation of VP1 in relation to Hsp90 in infected cells by indirect immunofluorescence and confocal microscopy.
- Full Text:
- Date Issued: 2016
The development of computational biology in South Africa: successes achieved and lessons learnt
- Mulder, Nicola J, Christoffels, Alan, De Oliveira, Tulio, Gamieldien, Junaid, Hazelhurst, Scott, Joubert, Fourie, Kumuthini, Judit, Pillay, Ché S, Snoep, Jacky L, Tastan Bishop, Özlem, Tiffin, Nicki
- Authors: Mulder, Nicola J , Christoffels, Alan , De Oliveira, Tulio , Gamieldien, Junaid , Hazelhurst, Scott , Joubert, Fourie , Kumuthini, Judit , Pillay, Ché S , Snoep, Jacky L , Tastan Bishop, Özlem , Tiffin, Nicki
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148347 , vital:38731 , DOI: 10.1371/journal.pcbi.1004395
- Description: Bioinformatics is now a critical skill in many research and commercial environments as biological data are increasing in both size and complexity. South African researchers recognized this need in the mid-1990s and responded by working with the government as well as international bodies to develop initiatives to build bioinformatics capacity in the country. Significant injections of support from these bodies provided a springboard for the establishment of computational biology units at multiple universities throughout the country, which took on teaching, basic research and support roles. Several challenges were encountered, for example with unreliability of funding, lack of skills, and lack of infrastructure. However, the bioinformatics community worked together to overcome these, and South Africa is now arguably the leading country in bioinformatics on the African continent. Here we discuss how the discipline developed in the country, highlighting the challenges, successes, and lessons learnt.
- Full Text:
- Date Issued: 2016
- Authors: Mulder, Nicola J , Christoffels, Alan , De Oliveira, Tulio , Gamieldien, Junaid , Hazelhurst, Scott , Joubert, Fourie , Kumuthini, Judit , Pillay, Ché S , Snoep, Jacky L , Tastan Bishop, Özlem , Tiffin, Nicki
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148347 , vital:38731 , DOI: 10.1371/journal.pcbi.1004395
- Description: Bioinformatics is now a critical skill in many research and commercial environments as biological data are increasing in both size and complexity. South African researchers recognized this need in the mid-1990s and responded by working with the government as well as international bodies to develop initiatives to build bioinformatics capacity in the country. Significant injections of support from these bodies provided a springboard for the establishment of computational biology units at multiple universities throughout the country, which took on teaching, basic research and support roles. Several challenges were encountered, for example with unreliability of funding, lack of skills, and lack of infrastructure. However, the bioinformatics community worked together to overcome these, and South Africa is now arguably the leading country in bioinformatics on the African continent. Here we discuss how the discipline developed in the country, highlighting the challenges, successes, and lessons learnt.
- Full Text:
- Date Issued: 2016
Allosteric modulation of conformational dynamics in human Hsp90α: a computational study
- Penkler, David L, Atilgan, Canan, Tastan Bishop, Özlem
- Authors: Penkler, David L , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/68531 , vital:29276 , http://dx.doi.org/10.1101/198341
- Description: Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by co-chaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. Here, we utilize homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially-open conformations. Atomistic simulations of these structures demonstrated that bound ATP stabilizes the dimer by ‘tensing’ each protomer, while ADP and apo configurations ‘relax’ the complex by increasing global flexibility. Dynamic residue network analysis revealed regions of the protein involved in intra-protein communication, and identified several overlapping key communication hubs that correlate with known functional sites. Perturbation response scanning analysis identified several potential residue sites capable of modulating conformational change in favour of interstate conversion. For the ATP-bound open conformation, these sites were found to overlap with known Aha1 and client binding sites, demonstrating how naturally occurring forces associated with co-factor binding could allosterically modulate conformational dynamics.
- Full Text:
- Date Issued: 2017
- Authors: Penkler, David L , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/68531 , vital:29276 , http://dx.doi.org/10.1101/198341
- Description: Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by co-chaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. Here, we utilize homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially-open conformations. Atomistic simulations of these structures demonstrated that bound ATP stabilizes the dimer by ‘tensing’ each protomer, while ADP and apo configurations ‘relax’ the complex by increasing global flexibility. Dynamic residue network analysis revealed regions of the protein involved in intra-protein communication, and identified several overlapping key communication hubs that correlate with known functional sites. Perturbation response scanning analysis identified several potential residue sites capable of modulating conformational change in favour of interstate conversion. For the ATP-bound open conformation, these sites were found to overlap with known Aha1 and client binding sites, demonstrating how naturally occurring forces associated with co-factor binding could allosterically modulate conformational dynamics.
- Full Text:
- Date Issued: 2017