From: kr%portal@cup.portal.com
Newsgroups: sci.nanotech
Subject: Re: What computer simulation can't do yet
Date: 28 Sep 92 00:56:36 GMT

ian@inf.ethz.ch (Ian) has written on 9/25/92:

->"One final note is that one
->"of the currently hot topics in protein design, the inverse protein
->"folding problem, was essentially invented by Drexler in 1982 while
->"at MIT...
->
->If  by  reverse  folding  you mean  "given  a  set  of  geometric 
->requirements  for the active-site of a protein, what sequence  is 
->required"  then (I think) the problem is a lot older  than  that.  
->After all people like Anfinsen were working on protein folding in 
->general  in 1973 (just the oldest reference that I had  to  hand) 
->and  I  don't  believe that they  never  considered  the  obvious 
->corollary.

There are a lot of obvious things that nevertheless seem to require an
unconventional intruder who brings them really to people's attention.
An example is PCR, which was invented by Kary Mullis after the
technological capabilities for implementing PCR have been hanging around
(unused for this purpose) for well over a decade...

Let me just quote from the published source itself
("Molecular engineering: An approach to the development of general
capabilities for molecular manipulation" by K. Eric Drexler, PNAS 78 (1981)
p.5275-5278):

"Indeed, chemists cannot yet predict the three-dimensional conformation of
a natural protein from its amino acid sequence, an ability that might seem
requisite to the design of new proteins. Two considerations suggest that this
obstacle is surmountable: first, the continuing improvement in protein science
and, second, the difference between natural science and design engineering."
..

"Regarding the second consideration, natural scientists seek a more general
understanding than design engineers require. Science seeks the ability to
predict the conformations of all natural peptides."
..

", natural selection accepts any folding process so long as the chain reaches
its natural conformation with essentially 100% yield."
..

"Thus, it is little wonder that chemists cannot yet predict the conformations
of natural proteins; they are not designed to fold predictably.
Engineers (in contrast to scientists) need not seek to understand all proteins
but only enough to produce useful systems in a reasonable number of attempts.
An engineer designing a protein that has 1000 amino acids may choose among some
10^1300 different amino acid sequences. It might be that only one in 10^9
(or even 10^700) randomly selected sequences would yield a predictable
conformation, yet this tiny fraction represents a vast number of proteins.
Through use of strategically placed charged groups, polar groups, disulfide
bonds, hydrogen bonds, and hydrophobic groups, the engineer should be able
to design proteins that not only fold predictably to a stable structure
(sometimes) but that serve a planned function as well. Even a low success rate
will lead to an accumulation of successful designs. Thus, the difficulties
encountered in predicting the conformations of natural proteins do not seem
insurmountable obstacles to protein engineering."

When he gives away copies of this paper nowadays, usually there is a note
attached, speaking even more clearly:

"Protein Engineering:
A 1988 view of some 1981 predictions

A 1981 paper [1] discussed de novo protein design as part of a long-term
{what a conservatively careful formulation:-) my commentary} strategy for
developing complex molecular devices and systems. It presented arguments
against the view that the fold-design problem is an extension of the classical
(and still unsolved) fold-prediction problem (i.e., predicting folds from
sequences without homologous models), a view which has discouraged efforts
at design.
Fold prediction is a scientific problem: it must deal with naturally evolved
sequences, but natural selection's 'design goals' enforce only the physical
reliability of folding - not its human predictability. This results in folds
of only minimal stability. Fold design, in contrast, is an engineering problem.
Protein engineers, exploiting their freedom of design, can work with sequences
artificially selected for superior predictability and stability of folding.
These observations indicated that "the difficulties encountered in predicting
the conformations of natural proteins do not seem insurmountable obstacles to
protein engineering"[1].
In accord with the implications of this argument, we have seen the successful,
de novo design of a globular protein (alpha4) [2,3] while the classical fold
prediction problem remains unsolved [4]. Likewise confirmed has been the 
suggestion that design can increase protein stability beyond that enforced
by natural selection. In recent years, deliberate single-residue modifications
have raised protein stabilities through a variety of mechanisms [5,6]. Owing
to design choices consistently biased towards stability, the protein alpha4
has a stability of 22kcal/mole, substantially greater than the 4-9 kcal/mole
of typical natural proteins of a similar size [3].
Successful protein engineering marks a milestone in a research agenda leading
toward capabilities of a broad technological significance [1,7].

References
[1] K.E.Drexler,"Molecular engineering: An approach to the development of
general capabilities for molecular manipulation." Proc.Nat.Acad.Sci.,78:5275-
5278 (1981)

[2] S.P.Ho and W.F.DeGrado,"Design of a 4-Helix bundle protein:Synthesis of
peptides which self-associate into a helical protein." J.Am.Chem.Soc.,109:6751-
6758 (1987)

[3] L.Regan and W.F.DeGrado,"Characterization of a helical protein designed
from first principles." Science,241:976-978 (1988)

[4] T.E.Creighton,"The protein-folding problem." Science,240:267,344 (1988)

[5] L.J.Perry and R.Wetzel,"Disulfide bond engineered into T4 Lysozyme:
stabilization of the protein toward thermal inactivation." Science,
226:555-557 (1984)

[6] B.W.Matthews, H.Nicholson, and W.J Becktel,"Enhanced protein thermostability
from site-directed mutations that decrease the entropy of unfolding."
Proc.Nat.Acad.Sci.,84:6663-6667 (1987), and included references

[7] K.E.Drexler,"Engines of Creation" Anchor/Doubleday (New York, 1986)"



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