One key step in biological synthesis of proteins is the translation of genetic code as carried by messenger ribonucleic acid (mRNA) into the correct sequence of amino acids that defines a given protein. There are 20 amino acids commonly used in protein synthesis and each has its unique tRNA. This charging is accomplished by enzymes called aminoacyl-tRNA synthetases, and one of the many questions with respect to their specificity is how they recognize their substrate tRNA molecules. Experimental studies have recognized key atomic groups in the sequence of the tRNA that carries amino acid alanine. In particular, substitution and/or modification of the first base pair in the amino acid acceptor stem eliminates alanine tRNA synthetase activity with respect to the mutant tRNA as a substrate. We performed molecular dynamics of both a natural (wild-type) and a modified (mutant) RNA hairpin that mimics the amino acid acceptor stem of alanine tRNA. The wild-type which has a G1:C72 base pair is recognized and charged by alanine tRNA, while switching to C1:G72 (mutant) it looses its activity completely. Our molecular dynamics simulations in aqueous solution indicate that the mutant RNA hairpin undergoes structural changes associated with base stacking. This is an important intramolecular interaction. This structural change may account for the enzymes's inability to recognize the mutant RNA. Our ongoing work has the goal of simulating structures for other mutants experimentally characterized as having various levels of activity and quantifying specific interaction energies of RNA with synthetase. The Computer Graphics Laboratory was used to visualize the structures in 3-D.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-24
Application #
6456731
Study Section
Project Start
2001-07-01
Project End
2003-08-31
Budget Start
Budget End
Support Year
24
Fiscal Year
2001
Total Cost
$273,230
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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