The determination of CHARMM force field parameters for the Mg2+ containing HIV-1 integrase:
- Musyoka, Thommas, Tastan Bishop, Özlem, Lobb, Kevin A, Moses, Vuyani
- Authors: Musyoka, Thommas , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
- Authors: Musyoka, Thommas , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
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
The evaluation and validation of copper (II) force field parameters of the Auxiliary Activity family 9 enzymes:
- Moses, Vuyani, Tastan Bishop, Özlem, Lobb, Kevin A
- Authors: Moses, Vuyani , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148206 , vital:38719 , DOI: 10.1016/j.cplett.2017.04.022
- Description: The Auxiliary Activity family 9 (AA9) proteins are Cu2+ coordinating enzymes which are crucial for the early stages of cellulose degradation. In this study, the force field parameters for copper-containing bonds in the Type 1 AA9 protein active site were established and used in a molecular dynamics simulation on a solvated, neutralized system containing an AA9 protein, Cu2+ and a β-cellulose surface. The copper to cellulose interaction was evident during the dynamics, which could also be accelerated by the use of high Cu O van der Waals parameters. The interaction of AA9, Cu2+ and cellulose is described in detail.
- Full Text:
- Date Issued: 2017
- Authors: Moses, Vuyani , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148206 , vital:38719 , DOI: 10.1016/j.cplett.2017.04.022
- Description: The Auxiliary Activity family 9 (AA9) proteins are Cu2+ coordinating enzymes which are crucial for the early stages of cellulose degradation. In this study, the force field parameters for copper-containing bonds in the Type 1 AA9 protein active site were established and used in a molecular dynamics simulation on a solvated, neutralized system containing an AA9 protein, Cu2+ and a β-cellulose surface. The copper to cellulose interaction was evident during the dynamics, which could also be accelerated by the use of high Cu O van der Waals parameters. The interaction of AA9, Cu2+ and cellulose is described in detail.
- Full Text:
- Date Issued: 2017
The generation and characterisation of neutralising antibodies against the Theiler’s murine encephalomyelitis virus (TMEV) GDVII capsid reveals the potential binding site of the host cell co-receptor, heparan sulfate:
- Upfold, Nicole, Ross, Caroline J, Tastan Bishop, Özlem, Luke, Garry A, Knox, Caroline M
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Luke, Garry A , Knox, Caroline M
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148181 , vital:38717 , DOI: 10.1016/j.virusres.2017.11.017
- Description: The early stages of picornavirus capsid assembly and the host factors involved are poorly understood. Since the localisation of viral proteins in infected cells can provide information on their function, antibodies against purified Theiler's murine encephalomyelitis virus (TMEV) GDVII capsids were generated by immunisation of rabbits. The resultant anti-TMEV capsid antibodies recognised a C-terminal region of VP1 but not VP2 or VP3 by Western analysis. Examination of the sites of TMEV capsid assembly by indirect immunofluorescence and confocal microscopy showed that at 5 h post infection, capsid signal was diffusely cytoplasmic with strong perinuclear staining and moved into large punctate structures from 6 to 8 h post infection.
- Full Text:
- Date Issued: 2018
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Luke, Garry A , Knox, Caroline M
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148181 , vital:38717 , DOI: 10.1016/j.virusres.2017.11.017
- Description: The early stages of picornavirus capsid assembly and the host factors involved are poorly understood. Since the localisation of viral proteins in infected cells can provide information on their function, antibodies against purified Theiler's murine encephalomyelitis virus (TMEV) GDVII capsids were generated by immunisation of rabbits. The resultant anti-TMEV capsid antibodies recognised a C-terminal region of VP1 but not VP2 or VP3 by Western analysis. Examination of the sites of TMEV capsid assembly by indirect immunofluorescence and confocal microscopy showed that at 5 h post infection, capsid signal was diffusely cytoplasmic with strong perinuclear staining and moved into large punctate structures from 6 to 8 h post infection.
- Full Text:
- Date Issued: 2018
The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype:
- Cornick, Jennifer E, Tastan Bishop, Özlem, Yalcin, Feyruz, Kiran, Anmol M, Kumwenda, Benjamin, Chaguza, Chrispin, Govindpershad, Shanil, Ousmane, Sani, Senghore, Madikay, du Plessis, Mignon, Pluschke, Gerd, 1952-, Ebruke, Chinelo, McGee, Lesley, Sigaùque , Beutel, Collard, Jean-Marc, Bentley, Stephen D, Kadioglu , Aras, Antonio, Martin, von Gottberg, Anne, French, Neil, Klugman, Keith P, Heyderman, Robert S, Alderson, Mark, Everett, Dean B
- Authors: Cornick, Jennifer E , Tastan Bishop, Özlem , Yalcin, Feyruz , Kiran, Anmol M , Kumwenda, Benjamin , Chaguza, Chrispin , Govindpershad, Shanil , Ousmane, Sani , Senghore, Madikay , du Plessis, Mignon , Pluschke, Gerd, 1952- , Ebruke, Chinelo , McGee, Lesley , Sigaùque , Beutel , Collard, Jean-Marc , Bentley, Stephen D , Kadioglu , Aras , Antonio, Martin , von Gottberg, Anne , French, Neil , Klugman, Keith P , Heyderman, Robert S , Alderson, Mark , Everett, Dean B
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148318 , vital:38729 , DOI: 10.1016/j.vaccine.2016.12.037
- Description: Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1.
- Full Text:
- Date Issued: 2017
- Authors: Cornick, Jennifer E , Tastan Bishop, Özlem , Yalcin, Feyruz , Kiran, Anmol M , Kumwenda, Benjamin , Chaguza, Chrispin , Govindpershad, Shanil , Ousmane, Sani , Senghore, Madikay , du Plessis, Mignon , Pluschke, Gerd, 1952- , Ebruke, Chinelo , McGee, Lesley , Sigaùque , Beutel , Collard, Jean-Marc , Bentley, Stephen D , Kadioglu , Aras , Antonio, Martin , von Gottberg, Anne , French, Neil , Klugman, Keith P , Heyderman, Robert S , Alderson, Mark , Everett, Dean B
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148318 , vital:38729 , DOI: 10.1016/j.vaccine.2016.12.037
- Description: Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1.
- Full Text:
- Date Issued: 2017
The In Silico Prediction of hotspot residues that contribute to the structural stability of subunit interfaces of a Picornavirus Capsid:
- Upfold, Nicole, Ross, Caroline J, Tastan Bishop, Özlem, Knox, Caroline M
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149970 , vital:38919 , https://doi.org/10.3390/v12040387
- Description: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid.
- Full Text:
- Date Issued: 2020
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Knox, Caroline M
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149970 , vital:38919 , https://doi.org/10.3390/v12040387
- Description: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid.
- Full Text:
- Date Issued: 2020
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
The role of structural bioinformatics in drug discovery via computational SNP analysis–a proposed protocol for analyzing variation at the protein level:
- Brown, David K, Tastan Bishop, Özlem
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162914 , vital:40996 , doi: 10.1016/j.gheart.2017.01.009
- Description: With the completion of the human genome project at the beginning of the 21st century, the biological sciences entered an unprecedented age of data generation, and made its first steps towards an era of personalized medicine. This abundance of sequence data has led to the proliferation of numerous sequence-based techniques for associating variation with disease, such as Genome-Wide Association Studies (GWAS) and Candidate Gene Association Studies (CGAS). However, these statistical methods do not provide an understanding of the functional effects of variation. Structure-based drug discovery and design is increasingly incorporating structural bioinformatics techniques to model and analyze protein targets, perform large scale virtual screening to identify hit to lead compounds, and simulate molecular interactions. These techniques are fast, cost-effective, and complement existing experimental techniques such as High Throughput Sequencing (HTS).
- Full Text:
- Date Issued: 2017
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162914 , vital:40996 , doi: 10.1016/j.gheart.2017.01.009
- Description: With the completion of the human genome project at the beginning of the 21st century, the biological sciences entered an unprecedented age of data generation, and made its first steps towards an era of personalized medicine. This abundance of sequence data has led to the proliferation of numerous sequence-based techniques for associating variation with disease, such as Genome-Wide Association Studies (GWAS) and Candidate Gene Association Studies (CGAS). However, these statistical methods do not provide an understanding of the functional effects of variation. Structure-based drug discovery and design is increasingly incorporating structural bioinformatics techniques to model and analyze protein targets, perform large scale virtual screening to identify hit to lead compounds, and simulate molecular interactions. These techniques are fast, cost-effective, and complement existing experimental techniques such as High Throughput Sequencing (HTS).
- Full Text:
- Date Issued: 2017
Understanding the Pyrimethamine drug resistance mechanism via combined molecular dynamics and dynamic residue network analysis:
- Amusengeri, Arnold, Tata, Rolland B, Tastan Bishop, Özlem
- Authors: Amusengeri, Arnold , Tata, Rolland B , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163022 , vital:41005 , https://doi.org/10.3390/molecules25040904
- Description: In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity.
- Full Text:
- Date Issued: 2020
- Authors: Amusengeri, Arnold , Tata, Rolland B , Tastan Bishop, Özlem
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163022 , vital:41005 , https://doi.org/10.3390/molecules25040904
- Description: In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity.
- Full Text:
- Date Issued: 2020
Unraveling the Motions behind Enterovirus 71 Uncoating:
- Ross, Caroline J, Atilgan, Ali R, Tastan Bishop, Özlem, Atilgan, Canan
- Authors: Ross, Caroline J , Atilgan, Ali R , Tastan Bishop, Özlem , Atilgan, Canan
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148158 , vital:38715 , DOI: 10.1016/j.bpj.2017.12.021
- Description: Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating.
- Full Text:
- Date Issued: 2018
- Authors: Ross, Caroline J , Atilgan, Ali R , Tastan Bishop, Özlem , Atilgan, Canan
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148158 , vital:38715 , DOI: 10.1016/j.bpj.2017.12.021
- Description: Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating.
- Full Text:
- Date Issued: 2018