Telephone : Cambridge 48011 1365 MEDICAL RESEARCH COUNCIL APR 5 LABORATORY OF MOLECULAR BIOLOGY, UNIVERSITY POSTGRADUATE MEDICAL SCHOOL, HILLS ROAD, CAMBRIDGE. 2nd April, 1965. Dr. Joshua Lederberg, Stanford University School of Medicine, Dept. of Genetics, 300 Pasteur Drive, Palo Alto, California, U.S.A. Dear Josh, I have not yet seen Holley's paper in Science, but I think I follow most of what you say. It is an old speculation that the S-RNA is so big because it may have to make a rather nicely balanced configurational change. However, it was assumed that this would come about when the amino acid was added. Your idea that it will only happen when the S-RNA combines with the correct codon is new to me. Alay I don't feel that there is anything hard to explain about the "Bernfield-Nirenberg" binding. You only have to assume that in addition to the binding energy between the codon and the anti-codon there is a weak general binding of S-RNA and codon to the ribosomes. I suspect that the binding between the codon and the anti-codon without the ribosome is too weak to be observable at all easily. Basically I think your idea a good one, but it may be hard to prove it, im [anwe F. H. C. Crick