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THE ROCKEFELLER UNIVERSITY

1230 YORK AVENUE NEW YORK, NY 10021

May 6, 1988

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JOSHUA LEDERBERG oe
PRESIDENT posh
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Professor Chen-Lu Tsou

Laboratory of Molecular Enzymology

Institute of Biophysics Yrr
Academia Sinica

Beijing 100080

China

 

Dear Professor Tsou:

I read with great interest your paper on protein folding
that appeared in Biochemistry, March 22, 1988. Although I
do not actively conduct research. in this field,your letter
raises issues that have been of very great interest to me for
the past 30 years.

If folding is concurrent with translation I would expect
that, as you say, post-translational adjustments would ensue
to bring the completed chain into its final, lowest energy
state.

I am going to raise a slightly different argument, how-
ever, about whether this final lowest energy state is the
biologically active state. As you point out the approach to
equilibrium from the renatured state may be a lengthy process
and in principle there may be kinetic constraints that will
require many hours or perhaps even virtually infinite time.

The plausible possibility that I then pose to you is that
Many proteins will be in their biologically active (and evo-
lutionary selected)conformation. for a period of seconds to
minutes after. translation is completed, but that they can then
undergo further transitions to the thermodynamic limit, which
is not necessarily biologically active. In that case there
will have been many frustrations to protein chemists seeking
to isolate proteins that retain their biologically active
conformation, when the equilibrium conformer, stable after
isolation and over long periods of storage,may well be bio-
logically inactive. ‘Certainly it is RQ part of the evolu- |
tionary process that protein. products r retain their most active
conformation to suit the convenience of biochemists.
Professor Chen-Lu Tsou
May 10, 1988

-2-

What I don't know is whether there is tangible experimen-
tal evidence to support this conjecture. Do you know of iso-
lations of purified proteins, preferably to crystallization,
that have been demonstrated to be in a conformation that
leaves them biologically inactive, although they have the

same primary structure as the biologically active product of
translation?

I am glad to see more attention given to the problem of
folding, particularly in. respect to its evolutionary impli-
cations. My own intuitive view is that the sequences we now
observe in organisms are very stringently selected so as to
permit folding to occur into a preferred conformer, in order
to avoid the inefficiencies that would obtain if there were
a wide variety of competing conformations that were kineti--
cally accessible and were approximately in the same energy
state. That is not inconsistent with the. "protein-isolators
‘dilemma" that I mentioned earlier in this letter. |

-¥ s_ sincerely,

   
 

oshua Lederberg

Encl. P80