The problem of how a 1-D poly peptide chain acquires the form
of a native 3-D protein structure is referred to as the protein folding
This is one of the most challenging and important research areas in
Biochemistry. All the information needed to specify the protein's 3-D structure
is contained within its amino acid sequence, and given suitable conditions,
most proteins will spontaneously fold into their native states.
Although studies have provided much information on the folding process,
our understanding of a way proteins fold is not full yet.
There are several methods to devise the 3-D structure of a protein:
The main reasons the protein folding problem is considered such a difficult
one are:if a protein had to search all the possible conformations to find
the energetically most favorable one, even a small protein would have to
search for an unreasonable amount of time. Since it is known that proteins
usually fold into their native states within much shorter time, it is clear
that the protein retains partially correct intermediate rather than randomally
scan all its possible conformations. Therefore, the energy calculations
involve millions of atomic interactions, and going over all of them to
find the most favorable conformation is beyond the ability of even the
most powerful computers available today.
Structure is much more conserved than sequence. Similar sequences usually
give similar structures, but different sequences may lead to a similar
structures. As a result, there is a much smaller number of known structures
than sequences. This means that the relationship between sequence and structure
is not one-to-one, and the tules that predict the structure out of the
sequence are not fully understood.
NMR (nuclear magnetic resonance)
Theoretical and computational methods:
Homology modeling assumes that similar sequence leads to similar
structure. It involves fitting a sequence to a known 3-D structure of a
similar sequence. Two proteins are considered homologous if they have identical
amino acid residues in a significant number of sequential positions along
the polypeptide chains (usually at least 30-40% of identity). The results
of homology modeling are more satisfying than those of ab-initio modeling
methods. About 2% of the known structures were determined this way.
Ab initio methods do not rely on known structures, rather they use
the physics of interactions among atoms, including the solvent, to define
a force field and then use methods like molecular dynamics or monte carlo
to determine the most stable structure.
threading (inverse folding): Since it is assumed that there is only
a limited number of stable folds and many different sequences having the
same fold, the inverse folding method tries to figure which specific patterns
are compatible with a specific fold. The used methodology is called threading,
since it involves "threading" a specific sequence through all known folds
and estimate the probability that the sequence can have such a fold.