| NSF Org: |
MCB Division of Molecular and Cellular Biosciences |
| Recipient: |
|
| Initial Amendment Date: | June 5, 2014 |
| Latest Amendment Date: | June 5, 2014 |
| Award Number: | 1412353 |
| 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: | June 1, 2014 |
| End Date: | May 31, 2017 (Estimated) |
| Total Intended Award Amount: | $298,682.00 |
| Total Awarded Amount to Date: | $298,682.00 |
| Funds Obligated to Date: |
|
| History of Investigator: |
|
| Recipient Sponsored Research Office: |
575 LEXINGTON AVE FL 9 NEW YORK NY US 10022-6145 (646)962-8290 |
| Sponsor Congressional District: |
|
| Primary Place of Performance: |
1300 York Avenue New York NY US 10065-4805 |
| Primary Place of
Performance Congressional District: |
|
| Unique Entity Identifier (UEI): |
|
| Parent UEI: |
|
| NSF Program(s): |
Molecular Biophysics, COMPUTATIONAL PHYSICS, Cross-BIO Activities |
| Primary Program Source: |
|
| Program Reference Code(s): |
|
| Program Element Code(s): |
|
| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.074 |
ABSTRACT
Ribosomes are molecular factories residing inside living cells responsible for reading genetic instructions originating in DNA and assembling proteins from amino acids based on these instructions. Ribosomes read genetic information by latching onto a long string-like molecule messenger RNA that contains the genetic instructions for one single protein molecule. The ribosome must convert the language of RNA into the language of protein. To accomplish this, the ribosome employs another class of RNA molecules called transfer RNA molecules, which convert the RNA alphabet into the protein alphabet. Much of ribosome research over the past 40 years has focused on the movement of transfer RNAs through the ribosome; however, the precise molecular mechanism has eluded researchers. It is only recently, with powerful supercomputers, single molecule imaging, and relevant atomic resolution structures, that this question can be addressed in atomic detail. Understanding how the ribosome works may lead to breakthroughs in the development of bio-inspired nanoscale computers, helping to fuel the nanotech industry. Understanding the ribosome may also lead to new insights into the origin of life and the origin of the genetic code.
The objective of this project is to study mechanism of ribosome head swivel using an integrated approach of molecular simulations and single molecule imaging. In head swivel, the head pivots around the neck, while the messenger RNA strand moves simultaneously around the neck and the transfer RNA moves through the inside of the ribosome. Simulations will be performed to understand the global motions of the ribosome occurring during head swivel. Detailed simulations will produce predictions for the energy landscape of head swivel. Fluorescent labels will be placed on the ribosome to monitor head swivel as a function of time using single molecule experiments. These same labels can be added into simulations to obtain comparisons between simulation and experiment and provide atomistic interpretations of the experiments.
This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Computational Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate.
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.
The ribosome is one of the largest and highly conserved molecular machines, whose function is essential to all life. Its operational principles, however, remain largely a mystery. Among the myriad of steps catalyzed by the ribosome during protein synthesis, translocation is considered the ‘holy grail’ by many. Translocation is an intrinsic property of the ribosome, involving complex conformational changes of the two ribosome subunits that move the mRNA and tRNA substrates by precisely three nucleotides in a unidirectional fashion. Our investigations into the mechanism of translocation on the bacterial ribosome revealed three distinct structural intermediates of translocation, two of which had not been previously observed. In addition, this work led to a key change in our understanding of the translocation mechanism. First, we showed that one of the two tRNA substrates can release from ribosome prior to complete translocation, whereas all prior studies investigating translocation had assumed that this was not the case. This finding fundamentally alters the field as it showed that the most critical barrier to movement pertained to the entry of peptidyl-tRNA into the P site (from the A site) was rate limiting to the translocation mechanism. Hence, the findings from the research performed led to critical revisions to the canonical mechanism of translocation on the bacterial ribosome that must now be further examined and scrutinized using independent lines of research, including those that probe the physiological impacts of the revised translocation mechanism as they pertain to regulation and antibiotic interventions.
Last Modified: 06/17/2017
Modified by: Scott C Blanchard
Please report errors in award information by writing to: awardsearch@nsf.gov.
