Highlights of our Work
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The ribosome is one of the largest molecular machines present in hundreds to thousands of copies in every cell, in charge of synthesizing every protein in the cell faithfully from genetic instruction. For this purpose the ribosome "reads" the sequence of bases on so-called messenger RNA, three bases at a time and depending on the base triple, the codon, elongates a nascent protein by one of 20 possible amino acids, avoiding to an impressive degree adding a wrong amino acid. So far one knew that the reading is done by transfer RNA molecules that have "foots" which match the possible codons and a "head" that brings along the associated amino acid. Each amino acid has its transfer RNA, the transfer RNAs checking if the next codon is "theirs," and if it is they add the proper amino acid to the nascent protein, elongating it. But how does the ribosome make the critical decision at the decoding center, namely if the transfer RNA "foot," the so-called anticodon, matches the codon? The answer is not known, but a key detail has now been discovered through a combination of electron microscopy and molecular dynamics simulation using NAMD, VMD, and a method called flexible fitting (MDFF, see the June 2008 highlight). It was known that a third molecular system is involved, called the elongation factor Tu (EF-Tu), which generates a key signal to the ribosome and transfer RNA through a chemical reaction. This reaction involves chemically attacking a substrate of EF-Tu, the molecule guanosine-triphosphate (GTP), with water, breaking a bond and turning GTP into guanosine-diphosphate (GDP). The puzzle was that EF-Tu is far away from the decoding center. The collaboration between experiment and simulation, reported here, revealed that "correct recognition" through anticodon-codon binding opens a gate in the EF-Tu that allows water access to the GTP inducing the signaling reaction. The finding promises to now establish how the decision at the decoding center is made and how an "open sesame" order is transmitted to EF-Tu. More on our ribosome website.