Submission information
Submission Number: 189
Submission ID: 4265
Submission UUID: db467bfe-878e-432d-905d-469f7c07ff7a
Submission URI: /form/project
Created: Wed, 12/20/2023 - 12:52
Completed: Wed, 12/20/2023 - 12:52
Changed: Wed, 04/02/2025 - 15:25
Remote IP address: 67.190.126.134
Submitted by: Anita Schwartz
Language: English
Is draft: No
Webform: Project
| Project Title | Discovering the Structure, Function, and Evolution of Sirtuins and Associated Proteins in Aiptasia: A Deep Learning and Integrative Genomics Approach |
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| Program | CAREERS |
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| Tags | deep-learning (303), genomics (537), hpc-tools (825), NSF ACCESS Resources (684) |
| Status | Complete |
| Project Leader | Milton Muldrow |
| milton.x.muldrow@wilmu.edu | |
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| Mentor(s) | Daniel Chauss |
| Student-facilitator(s) | Samantha Kidwell |
| Mentee(s) | |
| Project Description | We would like to further understand the structure and function of Sirtuins and functionally related proteins expressed by Aiptasia and evolutionarily compare across eukaryotic organisms. We plan to implement deep-learning methods as well as integrative genomic methods to further understand and map the interactively complex regulatory nature of Sirtuins during homeostasis and bleaching. One of our initial goals of our research program are to study Aiptasia protein interactions in silico via alphafold generated models using the colabfold implementation. In the future we hope to evolve these methods to consider physiological conditions such as those during various Aiptasia disease-states. Related: https://www.nature.com/articles/s41592-022-01488-1 Project goals include: Compare protein functional sites across taxa (ex: active and binding sites) to develop hypotheses regarding function Examine potential protein interactions (ex: NAD+) Predict evolutionary conservation and divergence Inform small molecule coral drug design if pathology is linked Mutations? How will DARWIN contribute? How We Will Leverage Former CAREERS progress: Student Natalie Vazques did a great job assisting in the establishment of the evaluation of coral/aiptasia proteins in our lab. Her work with BLAST will be leveraged as a starting point to further investigate attributes of coral sirtuin proteins. Natalie found there was significant similarity among coral/human/aiptasia sirtuin proteins, indicating overlapping function and potentially wide-ranging influence of these proteins. In this project, we will look to gain further insight into protein structure and potential function. Skills Students will gain: Structural Biology Research Deep Learning Applications Genomic Data Analysis Evolutionary Comparative Analysis High Performance Computing Research Skills Development Debugging Understanding Model organisms Teamwork and Collaboration Communication Skills Critical Thinking and Problem-Solving Symbiodinium microadriaticum strain:CCMP2467 (ID 292355) - BioProject - NCBI (nih.gov) Introduction: Sirtuins are a class of NAD+-dependent deacetylases that regulate a diverse set of biological processes including stress response, aging and metabolism. Sirtuins are found in every organismal kingdom, and are highly conserved throughout evolutionary time. Sirtuins are also found in the Aiptasia, an established animal model for corals. In this project, we seek to understand what influence sirtuins play in the complex bleaching process. This area of research is virtually unexplored given the likely importance sirtuins play in coral stress response. Also, there is a significant gap in knowledge regarding structural and function difference of sirtuins across diverse taxa. This research seeks to address this gap in knowledge by harnessing deep learning methodologies and integrative genomic techniques. Research Objectives and Methodology: Structural Analysis and Comparative Study of Functional Sites across Taxa: We will utilize AlphaFold software, via the ColabFold implementation, to generate high-resolution structural models of Sirtuins from Aiptasia and other species of interest. The computing power of DARWIN will enable us to run these programs and generate large data sets. This approach will enable us to investigate the structural conservation and divergence of these proteins and locate critical functional sites, such as active and binding sites. Comparative analysis of these sites across various taxa will inform hypotheses regarding the functional adaptations of Sirtuins. Protein-Protein Interaction and Metabolic Pathway Analysis: We aim to examine and identify partners of Sirtuins. This would include known partners, such as NAD+, but there is also the potential to identify new relationships. Integrating this knowledge with our structural data may facilitate the mapping of complex regulatory networks centered on Sirtuins. Investigation of Evolutionary Conservation and Divergence: By analyzing the sequence and structural data from various organisms, we will identify site changes in sirtuins over evolutionary time. Implications for Drug Design and Therapeutics: If our studies link Sirtuin-associated pathology to coral bleaching or other coral disease, this new will guide the rational design of small-molecule modulators targeting these proteins. There is potential for therapeutic interventions to combat coral bleaching. Assessment of the Impact of Mutations: By using both in silico models and potentially CRISPR/Cas9 gene editing in the future, we will study the effects of specific mutations on the structure, function, and interactions of Sirtuins. Sequencing: Our goal is to also run whole-genome experiments to best utilize DARWIN as well. This will be useful for population-level genetics. Conclusion: In accordance, the Darwin software will be utilized for the integrative analysis of structural, functional, and evolutionary data. As a cutting-edge tool for genomic data interpretation, Darwin will enhance our ability to gain insights from the immense amount of data generated in this project and facilitate the illumination of complex regulatory mechanisms. Our comprehensive and integrative approach will not only develop our understanding of Sirtuins in Aiptasia and across diverse animal taxa but also pioneer a new frontier in coral biology and conservation. Our findings could have profound implications for clarifying the mechanisms of coral bleaching and fostering innovations in coral reef restoration strategies. |
| Project Deliverables | |
| Project Deliverables | |
| Student Research Computing Facilitator Profile | |
| Mentee Research Computing Profile | |
| Student Facilitator Programming Skill Level | |
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| Project Institution | Wilmington University |
| Project Address | Wilmington, Delaware |
| Anchor Institution | CR-University of Delaware |
| Preferred Start Date | 01/10/2024 |
| Start as soon as possible. | No |
| Project Urgency | Already behind3Start date is flexible |
| Expected Project Duration (in months) | 6 months |
| Launch Presentation | |
| Launch Presentation Date | 02/16/2024 |
| Wrap Presentation | |
| Wrap Presentation Date | 11/13/2024 |
| Project Milestones |
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| What will the student learn? | (1) Understanding Sirtuins and Related Proteins. (2) Deep Learning and Genomic Methods. (3) Protein Interaction Studies Using AlphaFold. (4) Evolutionary Comparative Analysis. (5) Disease State Analysis and Drug Design. (6) Exploring Mutations and Their Impacts. (7) Research Skills Development. (8) Real-world Application. |
| What will the mentee learn? | |
| What will the Cyberteam program learn from this project? | Effort involved in recruiting and training |
| HPC resources needed to complete this project? | |
| Notes | |
| What is the impact on the development of the principal discipline(s) of the project? | Here, the student was able to perform some analyses we were long looking to conduct. Their work answered key questions regarding our research. Here, the student was able to conduct training on the DARWIN HPC system. Professor Muldrow (along with his son William Muldrow) was able to generate protein predictions for much of the Aiptasia proteome. From there, the student was able to learn important aspects of sirtuin protein structures and functions. At present, Professor Muldrow is working on papers that hypothesize sirtuin role and mechanisms of coral bleaching. Student Samantha has also participated in NASA Space Grant NNX15AII9H, which have overlaps goals, including understanding coral bleaching. The NASA work is focused on introducing Aiptasia to compounds that trigger NAD+ production, and thus, sirtuins. |
| What is the impact on other disciplines? | Examination of sirtuin genes may have broad implications of these highly conserved genes throughout the animal kingdom. This has potential implications in evolutionary biology along with human health. |
| Is there an impact physical resources that form infrastructure? | We were able to expand resources through accessing the DARWIN resource. |
| Is there an impact on the development of human resources for research computing? | N/A |
| Is there an impact on institutional resources that form infrastructure? | N/A |
| Is there an impact on information resources that form infrastructure? | N/A |
| Is there an impact on technology transfer? | N/A |
| Is there an impact on society beyond science and technology? | Our goal is to assist corals in becoming more resilient to climate change. If we are successful, this would have broad societal benefits, including economic, cultural and intrinsic benefits. From Samantha's Exit interview: Samantha indicated this CAREERS project provided her with the skills to be given the opportunity to work in the gene editing group at UD's Star Campus. |
| Lessons Learned | What went well? 1. Using our sequences from the lab to have more accurate information to run through AlphaFold and ColabFold 2. Using programs such as ChimeraX to visualize the protein and try to fit it with known Sirtuin proteins in human DNA 3. Utilizing DARWIN to check our information What could have been done differently? 1. Having a separate account for AlphaFold/ColabFold 2. Providing more storage for results |
| Overall results | Aiptasia Pallida Sirtuin 1 Comparison: 1. Use DARWIN to confirm AlphaFold/ColabFold accuracy 2. Compared Aiptasia sirtuin sample to human sirtuin samples 3. Using ChimeraX to visualize the similarities and differences. 4. Out of 268 atom pairs, 179 atom pairs align with human sirtuin 1 |