| NSF Org: |
MCB Division of Molecular and Cellular Biosciences |
| Recipient: |
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| Initial Amendment Date: | May 21, 2019 |
| Latest Amendment Date: | May 21, 2019 |
| Award Number: | 1915843 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Wilson Francisco
wfrancis@nsf.gov (703)292-7856 MCB Division of Molecular and Cellular Biosciences BIO Directorate for Biological Sciences |
| Start Date: | July 1, 2019 |
| End Date: | June 30, 2024 (Estimated) |
| Total Intended Award Amount: | $797,314.00 |
| Total Awarded Amount to Date: | $797,314.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
360 HUNTINGTON AVE BOSTON MA US 02115-5005 (617)373-5600 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
360 Huntington Ave, 540-177 Boston MA US 02115-5005 |
| 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: |
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| 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 focuses on understanding the molecular factors that govern gene expression. To this end, large-scale simulations will be applied to study how the ribosome can accurately and efficiently synthesize proteins. The production of proteins is essential for nearly all biological functions, making the ribosome one of the most important biological machines. While modern experiments can resolve static configurations of the ribosome, detailed simulations will allow the research community to understand how molecular structure enables specific biological function. This can reveal strategies for controlling cellular dynamics, as well as provide a "rule book" that can aid in the design of novel molecular-scale machines. This project will involve a range of activities that will provide introductory science seminars for high school students, valuable training experiences for undergraduate and graduate student researcher and workshops for experimental researchers.
Theoretical models will be developed and applied to identify the detailed role of localized, "diffuse" ions during ribosome function. Characterizing several critical substeps of the elongation cycle (tRNA accommodation, hybrid-state formation, translocation and domain rotations) will elucidate how the ionic environment shapes the energy landscape of the ribosome. This will help uncover the modes by which ions can enable conformationally-complex biological dynamics. With the high negative charge density of RNA, the dynamics of ribonucleoprotein assemblies rely critically on a locally diffuse ionic environment, which can lead to attraction between negatively charged RNA molecules. Accordingly, to fully characterize the energetics of large-scale biological assemblies, one must properly describe the statistical properties of the ionic environment. To address this challenge, simplified energetic models will be developed that employ all-atom resolution, as well as explicitly represented monovalent and divalent ions. Calibration of the energetic parameters will be established through comparison with experiments and explicit-solvent simulations of prototypical systems. These simplified models will then enable the simulation of large-scale (20-100 Angstroms) conformational transitions in the ribosome. This will implicate the influence of fluctuations/changes in local ionic distributions. While this study will focus on ribosome dynamics, the models and computational methods will be transferrable to a broad range of biological assemblies.
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.
This award focused on the study of complex molecular assemblies in the cell. We developed theoretical models to simulate massive assemblies (hundreds of thousands of atoms) that are critical for cellular life. The primary system of interest was the ribosome, which is the sole producer of proteins in the cell. Proteins are involved in essentially every aspect of biology. By identifying the precise ways in which the ribosome works, the study provides a foundation that will help guide the next generation of therapeutics, which can include applications in antibiotic design and possibly anti-cancer drug development. In addition to the ribosome, our methods have enabled the study of virtually any biomolecular system. Since the ribosome is an extremely complex assembly, it allowed us to refine our techniques so that they can be rapidly applied to other critical biological systems. To provide just one example, at the beginning of the pandemic, we were able to quickly simulate how the SARS-CoV-2 spike protein allows the virus to enter a cell. The theoretical predictions provided the first insights into how infection occurs, while subsequent experimental studies later confirmed the predicted dynamics. Through this, our efforts have identified novel strategies that can be employed to generate new vaccines that can provide protection against all know variants of concern.
In addition to providing precise scientific insights, this award has had a range of broader impacts on the scientific community and society. For the scientific community, this award supported workshops, the development of training material, online scientific resources and numerous educational opportunities for trainees. A major resource that was supported was the “SMOG” tools (https://smog-server.org), which enable a broad range of simulation methods. In addition, we developed and maintained the Ribosome Analysis Database (RAD; https://radtool.rc.northeastern.edu), which is the first comprehensive resources for the analysis of more than 2000 ribosome structures. More broadly, this award helped provide research opportunities for students from underrepresented groups, students from non-research-intensive colleges and community colleges. Through this, the award has helped expand of pool of highly-trained scientists and engineers in the United States.
Last Modified: 10/25/2024
Modified by: Paul C Whitford
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