1. Researchers developed a Si-tag fusion protein containing Si-tag, RGD, and His-tag to enable delivery of biomolecules like RGD onto silica surfaces for tissue engineering applications.
2. They expressed the fusion protein in E. coli and tested various purification methods, finding that rapid purification using silica nanoparticles was more effective than silica gel or IMAC.
3. Functionality assays using immunostaining and binding to silica nanoparticles confirmed the fusion protein retained its ability to bind silica surfaces. Further optimization of purification conditions is still needed to improve protein yield.
Poster Presentation: Vishakha Sharma and Adriana Compagnoni. Grace Hopper Celebration of Women in Computing (GHC 2013), Minneapolis, MN, October 2-5, 2013.
Los días 20 y 21 de octubre de 2016, la Fundacion Ramón Areces organizó un simposio internacional para analizar las 'Enfermedades raras de la piel: de la clínica al gen y viceversa'. El doctor Fernando Larcher Laguzzi, del CIEMAT-Universidad Carlos III de Madrid-IIS Fundación Jiménez Díaz, ejerció de coordinador.
1) The study examines the interactions between the chemokine interleukin-8 (IL-8) and its receptor CXCR1 using NMR spectroscopy.
2) Solution NMR was used to identify residues on both IL-8 and the N-terminal domain of CXCR1 that are responsible for their interaction. Binding of IL-8 to the N-terminal domain causes it to dissociate from lipid bilayers.
3) Solid-state NMR showed that the N-terminal domain of CXCR1 aligns with lipid bilayers, demonstrating an interaction. However, this interaction is disrupted when IL-8 binds, causing the complex to dissociate from the bilayer.
Cyclic di GMP signaling network in Legionella pneumophilaasslev
This presentation sums up a 3 years long research aimed to study the involvement of the ubiquitous bacterial cyclic di-GMP signaling network in Legionella\’s host infection and intracellular multiplication.
1. Researchers developed a Si-tag fusion protein containing Si-tag, RGD, and His-tag to enable delivery of biomolecules like RGD onto silica surfaces for tissue engineering applications.
2. They expressed the fusion protein in E. coli and tested various purification methods, finding that rapid purification using silica nanoparticles was more effective than silica gel or IMAC.
3. Functionality assays using immunostaining and binding to silica nanoparticles confirmed the fusion protein retained its ability to bind silica surfaces. Further optimization of purification conditions is still needed to improve protein yield.
Poster Presentation: Vishakha Sharma and Adriana Compagnoni. Grace Hopper Celebration of Women in Computing (GHC 2013), Minneapolis, MN, October 2-5, 2013.
Los días 20 y 21 de octubre de 2016, la Fundacion Ramón Areces organizó un simposio internacional para analizar las 'Enfermedades raras de la piel: de la clínica al gen y viceversa'. El doctor Fernando Larcher Laguzzi, del CIEMAT-Universidad Carlos III de Madrid-IIS Fundación Jiménez Díaz, ejerció de coordinador.
1) The study examines the interactions between the chemokine interleukin-8 (IL-8) and its receptor CXCR1 using NMR spectroscopy.
2) Solution NMR was used to identify residues on both IL-8 and the N-terminal domain of CXCR1 that are responsible for their interaction. Binding of IL-8 to the N-terminal domain causes it to dissociate from lipid bilayers.
3) Solid-state NMR showed that the N-terminal domain of CXCR1 aligns with lipid bilayers, demonstrating an interaction. However, this interaction is disrupted when IL-8 binds, causing the complex to dissociate from the bilayer.
Cyclic di GMP signaling network in Legionella pneumophilaasslev
This presentation sums up a 3 years long research aimed to study the involvement of the ubiquitous bacterial cyclic di-GMP signaling network in Legionella\’s host infection and intracellular multiplication.
RAS is one of the most frequently mutated oncogenes in human cancer. KRAS is the isoform most frequently mutated, which constitutes about 85% of RAS mutations. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years.
In the formulation of KRAS integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers. Medicilon provides KRAS-targeted drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services.https://www.medicilon.com/platform/kras/
The document discusses the molecular basis of the interaction between the plasma membrane and the Gγ2 protein subunit. It examines the importance of specific amino acids, combinations of amino acids, and post-translational lipid modifications on the membrane localization of Gγ2. Site-directed mutagenesis and confocal microscopy were used to study how mutations in Gγ2 affected its interaction with and localization to the plasma membrane. The results showed that specific basic amino acids, cysteine residues, and geranylgeranyl lipid groups were essential for the proper membrane localization of Gγ2.
An in-silico Approach to Identify Avian IgY as Potential Inhibitor of HIV Env...IRJET Journal
1. The document describes an in-silico study examining avian IgY antibody as a potential inhibitor of the HIV envelope glycoprotein gp120.
2. Homology modeling was used to generate 3D structures of the IgY antibody and gp120 antigen, which were then docked together computationally.
3. The results of the docking simulation identified various amino acid interactions between the IgY antibody and gp120 antigen binding sites that could block the interaction between gp120 and human CD4+ receptors, thereby inhibiting HIV infection.
Structural Studies of Aspartic Endopeptidase pep2 from Neosartorya Fisherica ...ijbbjournal
- The document describes the structural study of the aspartic endopeptidase pep2 protein from Neosartorya fisherica using homology modeling techniques.
- A 3D structural model of pep2 was generated based on its sequence similarity to proteinase A from Saccharomyces cerevisiae. The pep2 model was evaluated and found to have good stereochemistry and energy values.
- Homology modeling is an effective technique for predicting the 3D structure of a protein when an experimentally determined structure of a suitable template is available. This study provides insights into the structure of the pep2 protein.
Glycan Structural Analysis Throughout Biotherapeutic Development SGS
Glycosylation is a key structural and functional element found on a wide variety of biotherapeutics. As such, alterations in glycan profile can significantly affect the efficacy of a drug through, for example, half life in the bloodstream or biological activity as well as being a potential source of immunogenicity. The glycan profile can be selected and controlled through the choice of cell line as well as control of bioreactor conditions. The use of analytical techniques that provide structural data on this type of post translational modification are vital in the development and characterisation of biologics. Techniques in glycan structural characterisation are discussed in this presentation.
The document discusses using in silico tools to model and study the interactions between the LGP2 protein and RNA. It first generates a 3D structural model of full-length LGP2 using homology modeling based on the helicase domain of Hef as a template, and validates the model by flexible fitting into an existing LGP2 density map. Molecular docking and dynamics simulations are then used to predict RNA-binding residues in LGP2's helicase domain and examine the stability of the LGP2-RNA complex. The results suggest additional residues beyond those previously identified that may be important for RNA binding in the helicase domain groove region.
I presented two fascinating stories where Molecular Dynamics simulations contributed to enhancing our understanding of immunodeficiencies. In one of the projects, the treatment of patients could be improved. These slides were presented at the Basler Modeller Stammtisch, 26.02.2021
Welcome to the June 25-26, 2018 Workshop on – 2 Day Workshop on Transcriptomic Data Analysis….
Below you should see an embedded video stream. You can open the stream to fill the full screen to observe or join the workshop as a participant with the link that was emailed to you. If you did not get the link, use the chat box on the bottom right to request the link with your registered email ID.
This document discusses several genes related to stem cell pluripotency, including OCT4, SOX2, NANOG, and LIN28. It provides information on the functions of these genes obtained from searches of PubMed, NCBI Gene, and other bioinformatics databases. Details include OCT4's role in maintaining pluripotency, SOX2's interaction with OCT4 and DNA binding structure, alignments of NANOG mRNA and protein sequences between human and mouse, and conserved domains identified in human and mouse LIN28 proteins through BLAST and CDD searches.
This document reports the 1H, 13C, and 15N backbone resonance assignments of the 214 amino acid human DGCR8core protein (residues 493-706) determined using heteronuclear NMR spectroscopy. DGCR8core contains two tandem double-stranded RNA binding domains (dsRBDs) separated by a flexible linker that are required for recognizing and binding pri-miRNA substrates during miRNA biogenesis. The NMR assignments provide a foundation for further investigating the dynamics and RNA-binding properties of DGCR8core in solution. Secondary structure analysis using chemical shift indices matches the seven alpha helices and seven beta strands observed in the crystal structure of DGCR8core.
Homology Modelling through modeller and its analysis using Ramachandran Plot
Modeller practical. Full tutorial created by Zarlish Attique
https://salilab.org/modeller/
Characterization of monoclonal antibodies and Antibody drug conjugates by Sur...Merck Life Sciences
Watch the presentation of this webinar: https://bit.ly/3Pjpjvr
Highlights of this webinar:
- Surface plasmon resonance as a powerful tool for biologic characterization including mAbs and ADCs.
- SPR allows rapid binding analysis in real time without using labels for SARS-CoV-2 receptor binding domain mutations.
- Kinetic data is indicative of possible neutralizing activity allowed assessment of neutralizing ability of therapeutic monoclonal antibodies.
- The application can provide preliminarily efficacy information and facilitated mAbs/ACDs candidate selection process
Detailed description:
Characterization of therapeutic monoclonal antibodies (mAbs) or Antibody drug conjugates (ADCs) is challenging due to their ability to bind to a variety of proteins via their Fc and Fab domains, giving rise to diverse biological functions associated with each domain. The Fc domain of mAbs interacts with Fc receptors with varying affinities, which can influence biological processes such as Complement-dependent cytotoxicity (CDC) and Antibody-dependent cellular cytotoxicity (ADCC), transcytosis, phagocytosis, and/or serum half-life.
An important characteristic of an antibody is its Fc effector function. Antibodies can be engineered to obtain desired binding of the Fc region to Fc receptors expressed on effector cells. Hence, it is crucial to evaluate the binding interaction of mAbs/ADC with Fc receptors in the early phase of drug development to understand the potential biological activity of the product in vivo.
Surface Plasmon Resonance (SPR) is a powerful technique to establish binding kinetics in real-time, label free, and high sensitivity with low sample consumption. Along with target antigen binding, it is crucial to evaluate the binding interaction of antibodies and ADCs with Fc receptors. Our SPR case studies investigated the impact on binding kinetics of ADCs with different linkers and the binding interactions of SARS-CoV-2 spike protein variants and evaluated the neutralizing ability of therapeutic mAbs. SPR characterisation can be facilitated in all stages of the product life cycle to ensure the quality and safety of mAbs and ADCs.
Characterization of monoclonal antibodies and Antibody drug conjugates by Sur...MilliporeSigma
The document discusses characterization of antibodies and antibody-drug conjugates (ADCs) using surface plasmon resonance (SPR). It provides details on:
1. Using SPR to characterize binding kinetics of ADCs and determine effects of different linker types and drug-antibody ratios on antigen binding. SPR shows reduced but detectable binding for ADCs versus the unconjugated antibody.
2. An application of SPR to study binding interactions of SARS-CoV-2 spike protein and mutants with the ACE2 receptor and anti-spike antibodies. This can aid understanding of viral mutations and inform vaccine and drug development.
3. SPR is proposed as a method to screen binding kinetics of spike protein mutants to evaluate effects
We previously reported a CRISPR-mediated knock-in strategy into introns of Drosophila genes, generating an attP-FRT-SA T2A-GAL4-polyA-3XP3-EGFP-FRT-attP transgenic library for multiple uses (Lee et al., 2018a). The method relied on double stranded DNA (dsDNA) homology donors with ~1 kb homology arms. Here, we describe three new simpler ways to edit genes in flies. We create single stranded DNA (ssDNA) donors using PCR and add 100 nt of homology on each side of an integration cassette, followed by enzymatic removal of one strand. Using this method, we generated GFP-tagged proteins that mark organelles in S2 cells. We then describe two dsDNA methods using cheap synthesized donors flanked by 100 nt homology arms and gRNA target sites cloned into a plasmid. Upon injection, donor DNA (1 to 5 kb) is released from the plasmid by Cas9. The cassette integrates efficiently and precisely in vivo. The approach is fast, cheap, and scalable.
Pyrosequencing slide presentation rev3.Robert Bruce
Pyrosequencing was evaluated as an alternative to Sanger sequencing for HIV drug resistance genotyping. Three assays were designed to detect mutations in the protease gene using a 356 bp amplicon and three sequencing primers. The assays demonstrated good linearity and sensitivity below 5% in quantifying mixed bases. However, read lengths were limited due to signal degradation, making it difficult to sequence large amplicons. Overall, pyrosequencing showed promise as a method for HIV genotyping but further optimization was needed to improve read lengths and mixed variant detection.
Best possible natural ligands which were enlisted on NPACT website were screened ( aid of major drug likeness parameters - pkCSM) and docked with the 2OJG(Target protein) using autodock.
Analysis insight about a Flyball dog competition team's performanceroli9797
Insight of my analysis about a Flyball dog competition team's last year performance. Find more: https://github.com/rolandnagy-ds/flyball_race_analysis/tree/main
06-04-2024 - NYC Tech Week - Discussion on Vector Databases, Unstructured Data and AI
Round table discussion of vector databases, unstructured data, ai, big data, real-time, robots and Milvus.
A lively discussion with NJ Gen AI Meetup Lead, Prasad and Procure.FYI's Co-Found
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Similar to Comparative analysis of docking of RGS9 gene
RAS is one of the most frequently mutated oncogenes in human cancer. KRAS is the isoform most frequently mutated, which constitutes about 85% of RAS mutations. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years.
In the formulation of KRAS integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers. Medicilon provides KRAS-targeted drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services.https://www.medicilon.com/platform/kras/
The document discusses the molecular basis of the interaction between the plasma membrane and the Gγ2 protein subunit. It examines the importance of specific amino acids, combinations of amino acids, and post-translational lipid modifications on the membrane localization of Gγ2. Site-directed mutagenesis and confocal microscopy were used to study how mutations in Gγ2 affected its interaction with and localization to the plasma membrane. The results showed that specific basic amino acids, cysteine residues, and geranylgeranyl lipid groups were essential for the proper membrane localization of Gγ2.
An in-silico Approach to Identify Avian IgY as Potential Inhibitor of HIV Env...IRJET Journal
1. The document describes an in-silico study examining avian IgY antibody as a potential inhibitor of the HIV envelope glycoprotein gp120.
2. Homology modeling was used to generate 3D structures of the IgY antibody and gp120 antigen, which were then docked together computationally.
3. The results of the docking simulation identified various amino acid interactions between the IgY antibody and gp120 antigen binding sites that could block the interaction between gp120 and human CD4+ receptors, thereby inhibiting HIV infection.
Structural Studies of Aspartic Endopeptidase pep2 from Neosartorya Fisherica ...ijbbjournal
- The document describes the structural study of the aspartic endopeptidase pep2 protein from Neosartorya fisherica using homology modeling techniques.
- A 3D structural model of pep2 was generated based on its sequence similarity to proteinase A from Saccharomyces cerevisiae. The pep2 model was evaluated and found to have good stereochemistry and energy values.
- Homology modeling is an effective technique for predicting the 3D structure of a protein when an experimentally determined structure of a suitable template is available. This study provides insights into the structure of the pep2 protein.
Glycan Structural Analysis Throughout Biotherapeutic Development SGS
Glycosylation is a key structural and functional element found on a wide variety of biotherapeutics. As such, alterations in glycan profile can significantly affect the efficacy of a drug through, for example, half life in the bloodstream or biological activity as well as being a potential source of immunogenicity. The glycan profile can be selected and controlled through the choice of cell line as well as control of bioreactor conditions. The use of analytical techniques that provide structural data on this type of post translational modification are vital in the development and characterisation of biologics. Techniques in glycan structural characterisation are discussed in this presentation.
The document discusses using in silico tools to model and study the interactions between the LGP2 protein and RNA. It first generates a 3D structural model of full-length LGP2 using homology modeling based on the helicase domain of Hef as a template, and validates the model by flexible fitting into an existing LGP2 density map. Molecular docking and dynamics simulations are then used to predict RNA-binding residues in LGP2's helicase domain and examine the stability of the LGP2-RNA complex. The results suggest additional residues beyond those previously identified that may be important for RNA binding in the helicase domain groove region.
I presented two fascinating stories where Molecular Dynamics simulations contributed to enhancing our understanding of immunodeficiencies. In one of the projects, the treatment of patients could be improved. These slides were presented at the Basler Modeller Stammtisch, 26.02.2021
Welcome to the June 25-26, 2018 Workshop on – 2 Day Workshop on Transcriptomic Data Analysis….
Below you should see an embedded video stream. You can open the stream to fill the full screen to observe or join the workshop as a participant with the link that was emailed to you. If you did not get the link, use the chat box on the bottom right to request the link with your registered email ID.
This document discusses several genes related to stem cell pluripotency, including OCT4, SOX2, NANOG, and LIN28. It provides information on the functions of these genes obtained from searches of PubMed, NCBI Gene, and other bioinformatics databases. Details include OCT4's role in maintaining pluripotency, SOX2's interaction with OCT4 and DNA binding structure, alignments of NANOG mRNA and protein sequences between human and mouse, and conserved domains identified in human and mouse LIN28 proteins through BLAST and CDD searches.
This document reports the 1H, 13C, and 15N backbone resonance assignments of the 214 amino acid human DGCR8core protein (residues 493-706) determined using heteronuclear NMR spectroscopy. DGCR8core contains two tandem double-stranded RNA binding domains (dsRBDs) separated by a flexible linker that are required for recognizing and binding pri-miRNA substrates during miRNA biogenesis. The NMR assignments provide a foundation for further investigating the dynamics and RNA-binding properties of DGCR8core in solution. Secondary structure analysis using chemical shift indices matches the seven alpha helices and seven beta strands observed in the crystal structure of DGCR8core.
Homology Modelling through modeller and its analysis using Ramachandran Plot
Modeller practical. Full tutorial created by Zarlish Attique
https://salilab.org/modeller/
Characterization of monoclonal antibodies and Antibody drug conjugates by Sur...Merck Life Sciences
Watch the presentation of this webinar: https://bit.ly/3Pjpjvr
Highlights of this webinar:
- Surface plasmon resonance as a powerful tool for biologic characterization including mAbs and ADCs.
- SPR allows rapid binding analysis in real time without using labels for SARS-CoV-2 receptor binding domain mutations.
- Kinetic data is indicative of possible neutralizing activity allowed assessment of neutralizing ability of therapeutic monoclonal antibodies.
- The application can provide preliminarily efficacy information and facilitated mAbs/ACDs candidate selection process
Detailed description:
Characterization of therapeutic monoclonal antibodies (mAbs) or Antibody drug conjugates (ADCs) is challenging due to their ability to bind to a variety of proteins via their Fc and Fab domains, giving rise to diverse biological functions associated with each domain. The Fc domain of mAbs interacts with Fc receptors with varying affinities, which can influence biological processes such as Complement-dependent cytotoxicity (CDC) and Antibody-dependent cellular cytotoxicity (ADCC), transcytosis, phagocytosis, and/or serum half-life.
An important characteristic of an antibody is its Fc effector function. Antibodies can be engineered to obtain desired binding of the Fc region to Fc receptors expressed on effector cells. Hence, it is crucial to evaluate the binding interaction of mAbs/ADC with Fc receptors in the early phase of drug development to understand the potential biological activity of the product in vivo.
Surface Plasmon Resonance (SPR) is a powerful technique to establish binding kinetics in real-time, label free, and high sensitivity with low sample consumption. Along with target antigen binding, it is crucial to evaluate the binding interaction of antibodies and ADCs with Fc receptors. Our SPR case studies investigated the impact on binding kinetics of ADCs with different linkers and the binding interactions of SARS-CoV-2 spike protein variants and evaluated the neutralizing ability of therapeutic mAbs. SPR characterisation can be facilitated in all stages of the product life cycle to ensure the quality and safety of mAbs and ADCs.
Characterization of monoclonal antibodies and Antibody drug conjugates by Sur...MilliporeSigma
The document discusses characterization of antibodies and antibody-drug conjugates (ADCs) using surface plasmon resonance (SPR). It provides details on:
1. Using SPR to characterize binding kinetics of ADCs and determine effects of different linker types and drug-antibody ratios on antigen binding. SPR shows reduced but detectable binding for ADCs versus the unconjugated antibody.
2. An application of SPR to study binding interactions of SARS-CoV-2 spike protein and mutants with the ACE2 receptor and anti-spike antibodies. This can aid understanding of viral mutations and inform vaccine and drug development.
3. SPR is proposed as a method to screen binding kinetics of spike protein mutants to evaluate effects
We previously reported a CRISPR-mediated knock-in strategy into introns of Drosophila genes, generating an attP-FRT-SA T2A-GAL4-polyA-3XP3-EGFP-FRT-attP transgenic library for multiple uses (Lee et al., 2018a). The method relied on double stranded DNA (dsDNA) homology donors with ~1 kb homology arms. Here, we describe three new simpler ways to edit genes in flies. We create single stranded DNA (ssDNA) donors using PCR and add 100 nt of homology on each side of an integration cassette, followed by enzymatic removal of one strand. Using this method, we generated GFP-tagged proteins that mark organelles in S2 cells. We then describe two dsDNA methods using cheap synthesized donors flanked by 100 nt homology arms and gRNA target sites cloned into a plasmid. Upon injection, donor DNA (1 to 5 kb) is released from the plasmid by Cas9. The cassette integrates efficiently and precisely in vivo. The approach is fast, cheap, and scalable.
Pyrosequencing slide presentation rev3.Robert Bruce
Pyrosequencing was evaluated as an alternative to Sanger sequencing for HIV drug resistance genotyping. Three assays were designed to detect mutations in the protease gene using a 356 bp amplicon and three sequencing primers. The assays demonstrated good linearity and sensitivity below 5% in quantifying mixed bases. However, read lengths were limited due to signal degradation, making it difficult to sequence large amplicons. Overall, pyrosequencing showed promise as a method for HIV genotyping but further optimization was needed to improve read lengths and mixed variant detection.
Best possible natural ligands which were enlisted on NPACT website were screened ( aid of major drug likeness parameters - pkCSM) and docked with the 2OJG(Target protein) using autodock.
Similar to Comparative analysis of docking of RGS9 gene (20)
Analysis insight about a Flyball dog competition team's performanceroli9797
Insight of my analysis about a Flyball dog competition team's last year performance. Find more: https://github.com/rolandnagy-ds/flyball_race_analysis/tree/main
06-04-2024 - NYC Tech Week - Discussion on Vector Databases, Unstructured Data and AI
Round table discussion of vector databases, unstructured data, ai, big data, real-time, robots and Milvus.
A lively discussion with NJ Gen AI Meetup Lead, Prasad and Procure.FYI's Co-Found
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Beyond the Basics of A/B Tests: Highly Innovative Experimentation Tactics You...Aggregage
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The Building Blocks of QuestDB, a Time Series Databasejavier ramirez
Talk Delivered at Valencia Codes Meetup 2024-06.
Traditionally, databases have treated timestamps just as another data type. However, when performing real-time analytics, timestamps should be first class citizens and we need rich time semantics to get the most out of our data. We also need to deal with ever growing datasets while keeping performant, which is as fun as it sounds.
It is no wonder time-series databases are now more popular than ever before. Join me in this session to learn about the internal architecture and building blocks of QuestDB, an open source time-series database designed for speed. We will also review a history of some of the changes we have gone over the past two years to deal with late and unordered data, non-blocking writes, read-replicas, or faster batch ingestion.
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You can see the future first in San Francisco.
Over the past year, the talk of the town has shifted from $10 billion compute clusters to $100 billion clusters to trillion-dollar clusters. Every six months another zero is added to the boardroom plans. Behind the scenes, there’s a fierce scramble to secure every power contract still available for the rest of the decade, every voltage transformer that can possibly be procured. American big business is gearing up to pour trillions of dollars into a long-unseen mobilization of American industrial might. By the end of the decade, American electricity production will have grown tens of percent; from the shale fields of Pennsylvania to the solar farms of Nevada, hundreds of millions of GPUs will hum.
The AGI race has begun. We are building machines that can think and reason. By 2025/26, these machines will outpace college graduates. By the end of the decade, they will be smarter than you or I; we will have superintelligence, in the true sense of the word. Along the way, national security forces not seen in half a century will be un-leashed, and before long, The Project will be on. If we’re lucky, we’ll be in an all-out race with the CCP; if we’re unlucky, an all-out war.
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Before long, the world will wake up. But right now, there are perhaps a few hundred people, most of them in San Francisco and the AI labs, that have situational awareness. Through whatever peculiar forces of fate, I have found myself amongst them. A few years ago, these people were derided as crazy—but they trusted the trendlines, which allowed them to correctly predict the AI advances of the past few years. Whether these people are also right about the next few years remains to be seen. But these are very smart people—the smartest people I have ever met—and they are the ones building this technology. Perhaps they will be an odd footnote in history, or perhaps they will go down in history like Szilard and Oppenheimer and Teller. If they are seeing the future even close to correctly, we are in for a wild ride.
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2. Introduction of RGS9-protein
The official name of RSG9 gene is “Regulator of g-protein signaling 9.”
RGS9 gene encodes a member of the RGS family of GTPase(Guanosine Tri-
phosphatase) activating proteins that function in various signaling
pathways .
This protein is anchored to photoreceptor membranes in retinal cells and
deactivates G proteins in the rod and cone photo-transduction cascades.
Mutations in this gene result in bradyopsia, a rare condition that affects
vision.
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 2
3. Cont…
The RGS9 gene provides instructions for making two versions
(isoforms) of the RGS9 protein, known as RGS9-1 and RGS9-2. They
are found in different parts of the nervous system and have very
different functions.
RGS9-1 is produced in the retina, which is the specialized tissue at the
back of the eye that detects light and color.
Within the retina, RGS9-1 is associated with light-detecting cells called
photoreceptors. When light enters the eye, it stimulates specialized
pigments in these cells. This stimulation triggers a series of chemical
reactions that produce an electrical signal, which is interpreted by the
brain as vision. (This process is known as photo-transduction.)
Once photoreceptors have been stimulated by light, they must return
to their resting state before they can be stimulated again. RGS9-1 is
involved in a chemical reaction that helps return photoreceptors to
their resting state quickly after light exposure.COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 3
4. Location of Gene
RGS9 cytogenetic location is 17q24.
More precisely, the RGS9 gene is located from base pair
65,137,338 to base pair 65,227,703 on chromosome 17 on the
long (q) arm at position 24 .
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 4
5. Mutation identification
The Mutation occurred at position 299 where Threonine (T)
was replaced by Cysteine(C) which results in Bradyopsia, a
rare condition that affects vision.
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 5
6. 3D structure prediction of RGS9 and
Mutated RGS9
One of the best Models is to be selected on the basis of
RMSD value and its structure validation results, so Swiss-
Model server model is the best model which was generated
against same template “2pbi.2.A” for normal and mutated
Protein.
RSG9 CHIMERA view Mutated RSG9 CHIMERA view
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 6
7. Superimposition
We use Chimera for the superimposition of Normal
and Mutated protein. RMSD value of this
superimposition is 0.660 as shown below.
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 7
8. Domain Identification
Domains are the functional and structural units in a
protein.
They are responsible for a particular function or interaction
of a protein.
In order to identify the domains of RGS9 we used following
servers.
SERVERS USED DOMAIN NAME DOMAIN RANGE
Superfamily (HMM library &
genome environment
server)
Regulator of G-protein Signaling
(RGS)
59-189
ScanProsite RGS domain 73-188
Interpro (Protein seq
analysis & classification)
RGS domain 59-188
Motif Scan Result RGS domain 73-187
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 8
10. Binding Pocket Identification
Binding Pockets are the area of protein known to be active
in forming of compounds.
Castp Results
Binding sites and active sites of proteins and DNAs are
often associated with structural pockets and cavities as
shown below.
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 10
12. Retrieval of Binding Partners(Ligands)
For this purpose String database is used which allows
searching of protein-protein interaction of RGS9
protein. Results are shown below.
COMSATS INSTITUTE OF INFORMATION
TECHNOLOGY, ISLAMABAD 12
13. Selection of Ligand
Selected ligands on the basis of least no. of amino
acids in it.
Ligand
#
Name Description No. of Amino
acids
Pdb ID
1 GNAT1 Guanine nucleotide-binding proteins
(G proteins) are involved as
modulators or transducers in various
transmembrane signaling systems.
350 aa 2ju4
2 PDE6H Participates in processes of
transmission and amplification of the
visual signal. These are the effector
molecules in G-protein-mediated
photo-transduction in vertebrate rods
and cones.
83 aa 1got
COMSATS INSTITUTE OF INFORMATION
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14. Molecular Docking
When the ligand is docked onto the receptor and the
interactions are checked, the scoring function generates
scores depending on which the best fit ligand is selected.
For docking HEX server is used.
HEX server
HEX is an interactive protein docking and molecular
superposition program. The first 10 solutions are saved as
both.pdb for each docking.
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15. Result of Hex
COMPLEX# Normal
receptor with
ligand#1 (2ju4)
Normal
receptor with
ligand#2 (1got)
Mutated
receptor with
ligand#1 (2ju4)
Mutated
receptor with
ligand#2 (1got)
1 -749.46 -513.68 -653.47 -745.57
2 -697.18 -510.31 -647.83 -680.30
3 -693.69 -490.68 -639.52 -654.98
4 -691.90 -475.57 -631.21 -629.29
5 -689.50 -471.50 -623.87 -606.62
6 -660.35 -468.26 -621.84 -603.53
7 -652.47 -464.42 -620.93 -588.93
8 -646.40 -457.91 -614.65 -587.69
9 -643.44 -457.56 -608.78 -586.71
10 -643.37 -450.76 -606.47 -583.95
The Energy values of 10 solutions each is shown below
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16. Ligand#1 with Normal and Mutated Structure
Figure:
(A) Best solutions after docking of Ligand (2ju4) with Normal structure where E-value= -
749.46
(B) Best solutions after docking of Ligand (2ju4) with Mutated structure where E-value= -
653.47 COMSATS INSTITUTE OF INFORMATION
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17. Ligand#2 with Normal and Mutated Structure
Figure: (C) Best solutions after docking of Ligand (1got) with Normal structure where E-value=
-513.68
(D) Best solutions after docking of Ligand (1got) with Mutated structure where E-value= -
745.57
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18. Ligplot+ Results
The program automatically generates schematic
diagrams of protein-ligand interactions from the 3D
coordinates PDB file(Edited by PDB- Editer).
In figures Maroon eyelashes represents hydrophobic
interactions with receptor while
Pink eyelashes represents hydrophobic interactions with
Ligands.
Green dotted lines show Hydrogen bonding between
receptor and ligand.
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19. Ligplot+ output of Ligand#1 (2ju4) with Normal
structure
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20. Ligplot+ output of Ligand#1 (2ju4) with Mutated
structure
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21. Ligplot+ output of Ligand#2 (1got) with Normal
structure
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22. Ligplot+ output of Ligand#2(1got) with Mutated
structure
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23. CONCLUSION
The Protein-Ligand interaction plays a significant role in structural based drug
designing. By analyzing the HEX docking results it is concluded that after the
mutation occurs there is the desperate change between the E-values of same
protein normal protein and its mutated protein when respectively docked by
two ligands.
The Ligplot+ results that the hydrogen bonded residues and hydrophobic
residues of normal receptor with ligands are different from those of mutated
receptor that are involved in bonding with respective ligands.
Due to mutation in sequence at position 299 from T-C which resulted in the
change of binding position between the receptor and ligand as a result
Bradyopsia disease occurs.
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