Multi-drug resistant bacteria present an increasing problem in US hospitals. To design new antibiotics that are effective against these bacteria, it is important to understand drug-target interactions and the targets themselves. We will study a major antibiotic target: the ribosome. Many ribosome antibiotics interfere with the process of decoding by the ribosome (tRNA selection). The rate-limiting step of decoding is accommodation, where the tRNA moves from a partially bound state (A/T state) to its fully bound position (A/A state) inside the ribosome. Structural biology techniques have determined the structure of the ribosome before and after accommodation. Kinetic experiments have determined accommodation rates. It is difficult, however, to study the process of accommodation in atomic detail experimentally and the detailed effects of antibiotics. While molecular dynamics simulations have been used to characterize spontaneous transitions in smaller protein complexes, the large size and complexity of the ribosome have made similar studies of the ribosome computationally prohibitive. In our preliminary data, we have combined the high performance computing resources at Los Alamos National Laboratory with all-atom reduced-model potentials to study accommodation of tRNA into the ribosome. Here, we will use large- scale molecular simulation to study key features of accommodation and the effects of antibiotics. We will closely integrate molecular dynamics with single molecule studies to form a more coherent picture of ribosome decoding.

Public Health Relevance

Supercomputers will be used to simulate a major antibiotic target (the ribosome) in atomic detail. Atomistic and reduced-model molecular simulations will be used to understand ribosome conformational changes, and effects of antibiotics on these processes. Results will be closely integrated with single molecule data. Testable predictions will be made to guide future experiments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM072686-16
Application #
10157895
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sakalian, Michael
Project Start
2005-07-01
Project End
2024-12-31
Budget Start
2021-02-01
Budget End
2021-12-31
Support Year
16
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Triad National Security, LLC
Department
Type
DUNS #
080961356
City
Los Alamos
State
NM
Country
United States
Zip Code
87545
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