2 research outputs found
Deriving amino acid contact potentials from their frequencies of occurence in proteins: a lattice model study
The possibility of deriving the contact potentials between amino acids from
their frequencies of occurence in proteins is discussed in evolutionary terms.
This approach allows the use of traditional thermodynamics to describe such
frequencies and, consequently, to develop a strategy to include in the
calculations correlations due to the spatial proximity of the amino acids and
to their overall tendency of being conserved in proteins. Making use of a
lattice model to describe protein chains and defining a "true" potential, we
test these strategies by selecting a database of folding model sequences,
deriving the contact potentials from such sequences and comparing them with the
"true" potential. Taking into account correlations allows for a markedly better
prediction of the interaction potentials
Simple models of protein folding and of non--conventional drug design
While all the information required for the folding of a protein is contained
in its amino acid sequence, one has not yet learned how to extract this
information to predict the three--dimensional, biologically active, native
conformation of a protein whose sequence is known. Using insight obtained from
simple model simulations of the folding of proteins, in particular of the fact
that this phenomenon is essentially controlled by conserved (native) contacts
among (few) strongly interacting ("hot"), as a rule hydrophobic, amino acids,
which also stabilize local elementary structures (LES, hidden, incipient
secondary structures like --helices and --sheets) formed early
in the folding process and leading to the postcritical folding nucleus (i.e.,
the minimum set of native contacts which bring the system pass beyond the
highest free--energy barrier found in the whole folding process) it is possible
to work out a succesful strategy for reading the native structure of designed
proteins from the knowledge of only their amino acid sequence and of the
contact energies among the amino acids. Because LES have undergone millions of
years of evolution to selectively dock to their complementary structures, small
peptides made out of the same amino acids as the LES are expected to
selectively attach to the newly expressed (unfolded) protein and inhibit its
folding, or to the native (fluctuating) native conformation and denaturate it.
These peptides, or their mimetic molecules, can thus be used as effective
non--conventional drugs to those already existing (and directed at neutralizing
the active site of enzymes), displaying the advantage of not suffering from the
uprise of resistance