Mareh 24, 1965

De. Francis Crick
4xC Unit for “olecular Biology
Cambridge, England

Dear Francis--

After your talk, I thought some more about the mechanisms of t~-RNA. Farti-
cularly in mind were 1) why it is so big and 2) how Rernfield-Niereaberg binding
by trinucleotide to ribosome could work. When I saw the Holley paver in science
their figure 2 looked as if it would introduce the same hypothesis, but it didn't
quite, and I wonder i? the “following idea is current now:

The t-RNA can exist in 2 (or more) conforvations of nearly equal energy, but
one of these is prevalent in the absence of the codon, and this one does not
interact with the ribosome. The other is stabilized by adherence of the coon,
ani this conformation does interact with the ribosome. I can even imagine that
when the coon is an expose! triplet of m-RNA at the ribosome that it is the transi-
tion between the two states that excites the charged end to react with the trans‘er
enzyme which must be sitting at the growing point of the ocolynetide chain. The BH
effect may then be not the role of the trivlet as a coligan) ‘for the t-RNA ani the
ribosome, but an inducer to alter the conformation of the t-RNA to a state that
then fits the ribosome. This gets away from the dilemma how shch a short wk coJon
ean bind large molecules together.

The t-RNA is so big as the condition for a structure that can be armed so ex-
quisitely to be triggered by a small coijon, so specifically. 9 sumably one of the
alternative conformations allows for internal pairing of tae"BS4on with another
region of the same RNA molecule; in the other the vairing is competitevely satis-
fied by the codon. Until a few more sequences are available, the guessing is
hazardous, but in Holley's figure 2, one can see $hat the two right~nani alterna-
tives might just f111 the bill (if the central loop in the upper figure would not
readily acoomoate a bound codon). S£KEXKX Strikingly enough there are no GC* or
GCU sequences that might confound the anti-codon, go I would withdraw the ijea of
strict competitive paiting in favor of competing coniormations in one of which
codon-pairing is hindered.

Aly?

An advantage of one Term of this hypothesis is that one should see physical
evidence of the conformational shift by the interaction of t-RNA with codons vossibly
even in the absence of other components. Not many people have the material to
look at this yet.

Sincerel;, oe

Joshua Lederberg