PRELUDE & FUGUE
predict the local structure of a protein in
terms of backbone dihedral angle domains, identify sequence regions that form early during
folding, and locate structural weaknesses, defined as regions whose sequence
is not optimal with respect to the tertiary fold.
These programs use a statistical backbone torsion angle potential, which describes
local interactions along the chain and is derived from a set of 1403 known protein structures.
The input they require is the amino acid sequence of the target protein.
The output yields the predicted structures given in terms of 7 backbone torsion angle
assignments noted A, B, C, G, E, O, P; the phi, psi, and omega values associated to these assignments are given here
PRELUDE&Fugue predicts the N backbone conformations
of lowest energy of a protein
sequence or sequence segment, where N is specified by
the user. The user may impose constraints on some interatomic
distances in the predicted structures. The output file contains the
lowest energy structures that satisfy the constraints, the predicted energy
values, and the energy gap and root mean square (rms) deviation of
superimposed backbone atoms of each
predicted structure relative to
the lowest energy predicted structure. In addition, the 3D structures of
all the predicted conformations are supplied in PDB format.
A sequence whose lowest energy conformation displays a sizable energy gap
relative to other predicted structures is considered to have a well defined
preferred conformation. The program is designed to run mainly on short peptides,
because it only considers local interactions along the chain and
overlooks tertiary interactions. When applied to longer peptides, the
predictions must be considered as 2D rather than 3D and similar
to secondary structure predictions.
predicts the backbone structure, not of the whole input
sequence, but of those segments whose lowest energy structure is
strongly preferred over other conformations. The strength of the prediction
is given by a weight between 1 and 9.
Regions predicted by Fugue, with high weights, have an strong intrinsic
preference for their predicted conformation in the absence of tertiary interactions. When
cut from the sequence, the peptides so obtained are likely to adopt preferentially
this conformation in water at low temperature or in an apolar medium. When
considered within the sequence, these regions
can be exepected to form at the very beginning of the folding process.
Regions where the predicted structure differs from the native structure are
likely to be regions whose instrinsic structural preference, determined by
local interactions along the chain, are modified due to tertiary
interactions. They are interpreted as structural weaknesses, which possibly
slow down folding and cause alternative structuring.
Prediction of protein backbone conformation based on seven structure
assignments. Influence of local interactions.
Rooman MJ, Kocher JP, Wodak SJ.
J Mol Biol. 1991 Oct 5;221(3):961-79.
Extracting information on folding from the amino acid sequence: accurate
predictions for protein regions with preferred conformation in the absence of tertiary interactions.
Rooman MJ, Kocher JP, Wodak SJ.
Biochemistry. 1992 Oct 27;31(42):10226-38.
Using Prelude&Fugue as a 2D structure prediction method
For an assessment of the performances, click here
Using Prelude&Fugue to determine peptides that adopt a preferred
conformation in solution
For an example where Prelude
were used to propose sequences of
helical peptides, which were synthesized and shown by CD and NMR to be indeed helical in a mixture of
water and TFE at room temperature, see:
Conformational properties of four peptides corresponding to alpha-helical
regions of Rhodospirillum cytochrome c2 and bovine calcium binding protein.
Pintar A, Chollet A, Bradshaw C, Chaffotte A, Cadieux C, Rooman MJ, Hallenga
K, Knowles J, Goldberg M, Wodak SJ.
Biochemistry. 1994 Sep 20;33(37):11158-73.
Using Prelude&Fugue to identify early folding regions
For an analysis of the conservation of segments predicted to have well defined
instrinsic structural preferences in families
of homologous regions, and for a comparison with experimental data on early
folding intermediates, see:
Extracting information on folding from the amino acid sequence: consensus
regions with preferred conformation in homologous proteins.
Rooman MJ, Wodak SJ.
Biochemistry. 1992 Oct 27;31(42):10239-49.
Using Prelude&Fugue to identify structural weaknesses
Prelude&Fugue have been applied to proteins known to adopt alternative
structures that provoke conformational diseases or correspond to 3D domain swapping.
In these proteins, sequence regions have been detected whose intrinsic preferred conformations
differ from the native conformation, and could represent
structural weaknesses that facilitate misfolding. For an application to the amylodoigenic prion proteins, see :
PoPMuSiC, an algorithm for predicting protein mutant stability changes:
application to prion proteins.
For an application to proteins that undergo 3D domain swapping, see :
Gilis D, Rooman M.
Protein Eng. 2000 Dec;13(12):849-56.
Sequence-structure signals of 3D domain swapping in proteins.
Dehouck Y, Biot C, Gilis D, Kwasigroch JM, Rooman M.
J Mol Biol. 2003 Jul 25;330(5):1215-25.