
NSF Org: |
MCB Division of Molecular and Cellular Biosciences |
Recipient: |
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Initial Amendment Date: | May 24, 2018 |
Latest Amendment Date: | March 6, 2024 |
Award Number: | 1817670 |
Award Instrument: | Standard Grant |
Program Manager: |
Jaroslaw Majewski
MCB Division of Molecular and Cellular Biosciences BIO Directorate for Biological Sciences |
Start Date: | June 1, 2018 |
End Date: | August 31, 2024 (Estimated) |
Total Intended Award Amount: | $266,149.00 |
Total Awarded Amount to Date: | $281,677.00 |
Funds Obligated to Date: |
FY 2024 = $15,528.00 |
History of Investigator: |
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Recipient Sponsored Research Office: |
2000 PENNINGTON RD EWING NJ US 08618-1104 (609)771-3255 |
Sponsor Congressional District: |
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Primary Place of Performance: |
2000 Pennington Road Ewing NJ US 08628-0718 |
Primary Place of
Performance Congressional District: |
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Unique Entity Identifier (UEI): |
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Parent UEI: |
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NSF Program(s): | Molecular Biophysics |
Primary Program Source: |
01001819DB NSF RESEARCH & RELATED ACTIVIT |
Program Reference Code(s): |
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Program Element Code(s): |
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Award Agency Code: | 4900 |
Fund Agency Code: | 4900 |
Assistance Listing Number(s): | 47.074 |
ABSTRACT
This project will use advanced computational approaches to better understand the biomechanical properties of a protein filament that has applications ranging from bionanotechnology to cell motion and bacterial infection. Bacteria and archaea can adhere to surfaces using long, "sticky" filaments that protrude from their cell membranes called type IV pili (T4P). These filaments, which are made of thousands of copies of a protein called pilin, are incredibly strong, yet simultaneously extremely flexible. For example, a single bacterial T4P filament can support up to 10,000 times a bacterium's body weight, and T4P can be stretched to three times their original length without breaking. This project will use a computational approach known as molecular dynamics simulation to investigate the structure and dynamics of T4P filaments. Using this computational approach, simulated forces will be applied to T4P filaments to probe how they respond to being stretched, which will allow the identification of interactions that provide T4P with their great strength. The insights about T4P that will result from this work will inform applications in bionanotechnology, the role that T4P play in bacterial adhesion and motion, and will expand our general knowledge about protein filaments. Furthermore, this project will provide significant training to undergraduate students in a highly cross-disciplinary area of research at the interface of biology, physics, chemistry, and computer science. It will also develop computational learning modules and incorporate them into the undergraduate science curriculum to train students in the computational methods that are increasingly important in all scientific fields.
This project uses a computation/theory-led approach to: (1) investigate the dynamics of T4P filaments from three organisms, N. gonorrhoeae, N. meningitidis, and P. aeruginosa, at the all-atom level of resolution using all-atom molecular dynamics simulation, and (2) develop coarse-grained models to study the structural properties of T4P filaments, including the structural transition that occurs for T4P under external force. This comprehensive, multi scale computational approach will provide insights into the strength and dynamics of T4P across multiple length and time scales relevant to T4P function, and importantly will bridge the gap in knowledge that currently exists between the experimental and theoretical understanding of the biomechanics of T4P filaments. Specifically, all-atom simulations will be used to characterize T4P structural heterogeneity and to identify the most important interactions between pilin subunits for maintaining T4P structural integrity in the initial stages of the polymorphic transition that T4P exhibit under the application of external force. External forces will be applied to T4P using steered molecular dynamics protocols. Additionally, all-atom and coarse-grained simulations will be used in combination to determine important T4P filament properties such as the Young's modulus, persistence length, and torsional rigidity. Finally, coarse-grained simulations of T4P filaments under force will allow for the development of the first model of the fully force-transitioned state of a T4P filament, providing unprecedented molecular-scale insights into how the filament changes shape at the molecular scale. The coarse-grained T4P model developed in this project will act as a starting model for bridging from the atomistic scale to the scale of cellular biology. This project will provide novel insights into T4P biomechanics, aid in the fundamental understanding of the role of T4P in prokaryotes, and improve understanding of the plasticity of helical biopolymers.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Bacteria and other single-celled organisms use tiny, hair-like structures called pili to stick to surfaces, interact with their environment, and even move around. These pili, which are composed of proteins, are surprisingly strong - some types, like Type IV pili, can support many times the organism's own weight - yet they are also remarkably flexible. This combination of both strength and flexibility makes them fascinating to understand. Pili are also important to study as they can lead to persistent infection through their adhesive abilities, and are essential in forming bacterial biofilms. Because of their unique properties, understanding pilus biophysics can inform on the creation of new kinds of biomaterials for use in medicine and engineering.
The primary goal of this project has been to apply molecular simulation methods to understand the fundamental biophysics of bacterial pili, while engaging undergraduate students in research experiences at The College of New Jersey. The PI and his team of students have used very powerful supercomputers to build models of bacterial pili, and to calculate their motion at the level of every atom using computer simulations. By doing so, they have been able to reveal secrets behind pilus strength and flexibility. In particular, they have been able to understand how various pilus filaments respond to the effects of force, and to determine the most important interactions within pilus filaments responsible for maintaining their overall structural integrity. Essentially, the PI's team has experimented on the computer with pulling and stretching on bacterial pili to understand how they can fail when under stress. The methods developed to simulate these pili under stress has been applied to many pilus filaments and has provided a greater understanding of pilus mechanics. The project has led to several scientific publications, and has generated substantial data which will lead to additional future publications including student authors. The PI has also established very strong collaborations with expert experimentalist groups in the area of pilus structure and biophysics. This has greatly benefited the PI's students through their interactions with a team of scientists that would not be accessible to them at a primarily undergraduate institution alone.
Another major outcome of this project has been an impactful structural change in our chemistry curriculum through the development and implementation of computational chemistry modules. These modules introduce students to computational chemistry as early as their first semester at TCNJ when they take general chemistry, and are then embedded into many of our other courses including organic chemistry, thermodynamics, quantum chemistry, inorganic chemistry, biochemistry, as well as advanced elective courses. This has also involved training of faculty to be able to not only implement the computational chemistry modules, but also to develop new ones with the PI and even on their own. Due to the widespread use of computational chemistry in the curriculum, hundreds of undergraduates per year are exposed to these concepts and tools, which is critically important as their use continues to increase across all areas of the chemical and biophysical enterprise. The PI has also presented and published on this aspect of the project at the local, regional, and national levels.
The PI has been deeply committed to engaging undergraduates in closely mentored research, which is critical to developing the next generation of scientists and for providing deep intellectual growth for students as they pursue their degrees. This award supported the training of 27 undergraduate students to learn about molecular dynamics (MD) simulations to investigate the dynamics of bacterial pili models under force. Therefore, beyond the scientific findings, this work has provided transformative research experiences for a diverse group of undergraduate students, preparing them for successful careers in STEM fields. Because of its computational focus, it has also provided students with skills in high performance computing, modeling, and data analysis, that are critical for students entering a modern workforce. The 27 students trained have included 19 women, and 8 students who identified as first-generation in their family to pursue any college degree, and 5 who identified as members of underrepresented groups in the sciences. So far, 1 of the students has finished their PhD in biophysics, 2 have finished Masters degrees, 6 are currently pursuing PhDs in the sciences, 5 students are currently applying for PhD programs in the sciences, 2 are working in health fields, 7 are in the process of applying to MD and/or MD/PhD programs, and 5 are currently working in industry or planning to apply to industry jobs in the near future. They have also presented their work at numerous local, regional, and national conferences and have won awards for their work. Importantly, the research program this award has supported in the PI's research group at TCNJ will continue to benefit students, as they advance our understanding of bacterial adhesion through cutting-edge molecular simulations and collaborations with leading experimentalists.
Last Modified: 12/20/2024
Modified by: Joseph Baker
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