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PEKING, CHINA Institute of Biophysics

ACADEMIA SINICA

June 2, 1988

    
   

 

Dr. Joshua Lederberg
President

The Rockefeller University
1230 York Avenue

New York, NY 10021

U. S. A.

Dear Dr. Lederberg,

Thank you for your letter of May 6 and I am sorry for the
delay in answering as I was abroad for a couple of weeks.

Your letter raised a very important question in that "whether
the final lowest energy state is the biologically active state".
This has been usually assumed to be the case because, in vivo as
well as in vitro, most proteins so far studied are sufficiently
stable, and they do not seem to pass spontaneously into an
inactive confromational state. If indeed such states do exist, the
kinetic barrier between the metastable and biologically active
state and this stable but inactive state must be sufficiently
great so as to make the formation of the latter a very slow
process.

Some proteins are not very stable after isolation and the
‘reason is still poorly understood. Contamination by trace amounts
of proteolytic enzymes, chemical changes such as deamidation or
cleavage of susceptible peptide bonds have been suggested. As
crystallization, especially growth of crystals suitable for X-ray
diffraction studies, is usually a slow process, it would be
difficult to crystallize a partially "denatured" protein. Of
course, as you pointed out, precisely because of the instability
of biologically active conformers, some proteins may have escaped
detection by protein chemist when they seek to isolate an active
protein from the cell. |

Evolutionally, it might be of advantage for some proteins to
have a transient existence during life's processes. It is known
that the in vivo "half-life" differs greatly for different
p. 2. Dr. Lederberg.

proteins. It has been suggested that information stored in the
sequence of the protein molecules concerned directs their
breakdown. On first thought, it may not be advantageous, as far
as evolution is concerned, to have large amounts of. inactive
conformers linger around in the cell.

The above are the points that come to my mind after reading
your letter. However, I believe that the question you raised is of
such importance that careful consideration is required to do its
justice. It would also be of great importance to think of some
thing to do experimentally to elucidate some of the points as
discussed above.

I come to the States fairly often and invited by the late
Professor S. Moore, I had the honor to visit and to present a
Seminar at the Rockefeller University in 1981 when I was Visiting
Professor at Harvard Medical School with Bert Vallee. I am at
present a Fogarty Scholar-in-Residence at the NIH and shall be
spending my last term for a few months some time in the Spring of
1989 in Bethesda. I should be delighted to have an opportunity to
meet and to discuss matters of common interest with you when I
shall be in the States again.

Yours sipcerely

CX ba

C. L. Tsou,