1. Random sequences
and unique protein structures
Physical theory shows that a substantial fraction (~10-4
- 10-8 %) of
random amino acid sequences can form unique stable 3-D structures
under physiological conditions, fold rapidly, and have
typical for protein molecules. The main peculiarity of a
like" chain is a considerable gap dividing the energy of its
energy fold from the energies of the other folds; this gap plays
an essential role in thermodynamics and kinetics of folding.
2. How can a protein chain
find its unique fold?
The problem of how a protein chain can find its most stable
without exhaustive sorting out of all its possible conformations
as the "Levinthal paradox". I shall show in the lecture
that attaining of
the lowest-energy fold is rapid when it occurs in a vicinity of a
thermodynamic "all-or-none" transition from the coil to
energy fold. Such a transition requires an "edited"
chain with an
enhanced stability of its lowest-energy fold. In a vicinity of
transition point, all the mis- and semi-folded states cannot
folding since, even taken together, all these states are less
both the initial coil and the final stable fold of the chain.
stable fold can be rather rapidly achieved here via that
growth" folding pathway which provides a continuous
compensation in the course of folding, thus providing a low
state free energy. In the mid-transition, an N-residue chain
folds normally in ~exp(N 2/3) nsec. Therefore, a
normally finds its most stable fold within minutes rather than in
10100 psec ~ 1080 years, according to the
famous paradoxical estimate of Levinthal.
3. Introduction to protein
This is a review of the state of the art in the recognition and
prediction of protein folds from their sequences. I pay a special
attention to physical background of the predictive methods. In
particular, I review the secondary structure predictions and the
"threading" methods used for recognition of protein
folds. It is shown
that all the predictive methods can use only some part of the
interactions operating in the chain, and that even their energies
not known precisely. This is the principal source of errors and
uncertainties. The errors can be reduced by employment of many
homologs, but this opens only a possibility to predict a
structure and a generalised folding pattern rather than a
fold of a given chain with all details of the fold.