PROTAL - Protein Structure Prediction and Accurate Alignment of Protein
Sequences and Structures
by Heinz Mevissen, Joachim Selbig, Ralf Thiele, Ralf Zimmer and Thomas
Lengauer
The PROTAL project focuses on the development of computer-aided,
theoretical prediction methods for structure and function of given protein
sequences. The three-dimensional structure of proteins determines their
biochemical function in organisms in a complex process network of interactions
and regulations. Theoretical prediction methods try to shortcut labour-intensive,
time-consuming and expensive experimental structure determination in order
to reduce the increasing gap between the large number of of sequenced proteins
produced within genome and large scale sequencing projects and known protein
structures. Especially, predictions and modeling of binding and active
sites of particular proteins are of interest for biotechnology and pharmaceutical
industry.
The PROTAL project aims at the development of scoring schemes and methods
to support the construction of structural models for protein sequences
based on the homology modeling paradigm, ie inferring partial structures
from similarities with experimentally determined protein structures. The
scoring schemes and algorithmic methods are integrated in a software package
ToPLign (TOolbox for Protein aLIGNment).
The PROTAL project develops new hypotheses and models for factors determining
protein structure, which are essential as scoring schemes for prediction
methods. Especially new empirical potentials for amino acid interactions
are derived from databases of experimentally determined structures. In
order to appropriately model such interactions we developed a new contact
definition based on Voronoi tesselations of protein structures. The potentials
are used for the identification of appropriate targets as well as the computation
of structurally compatible alignments.
Protein fold recognition allows the rapid identification of evolutionary,
structurally, or functionally related proteins of known structure, so called
targets. Accurate homology modeling of such proteins requires high quality
alignments of the sequences in question to identified target structures.
Refined alignments specify the coordinates of identically matched amino
acids and determine amino acid side chains to be placed and backbone loop
regions to be modeled.
A significant sequence similarity between sequences of unknown structure
and known protein families is demonstrated via extended and new methods
for the visualization and reliability of alignments, for tree and clustering
multiple profile alignments, and for the computation of all compatible
phylogenetic trees together with their associated multiple alignments.
New threading approaches are developed in order to show sequence-structure
compatibility: The 123D threading method computes optimal alignments with
respect to so-called contact capacity potentials (CCP). These potentials
represent a detailed measure for hydrophobicity and contact environments.
The RDP (recursive dynamic programming) threading algorithm is used to
refine computed alignments and structural models. The method concentrates
on the most important regions of the protein and optimizes the mapping
recursively. The procedure optimally extends subalignments by dynamic programming
with respect to a full pair interaction potential of already mapped parts.
For all alignment and threading methods the inherent inaccuracy of biological
data has to be taken into account in the methods and their statistical
validation. In order to analyse the dependency of alignments on the parameters
of the scoring scheme we use a new parametric optimization method, which
is able to compute, for a given algorithm and type of scoring function,
all different optimal alignments over the whole range of parameter settings.
This allows for the systematic evaluation of competing methods and for
insights into the reliabilty of computed alignments.
The Figure shows our successful ToPLign prediction of the structure
for the active site of the thymidine kinase of the herpes virus, which
is important for the development of inhibitors. The sequence was kindly
provided by BASF AG. The developed methods have also been successfully
applied in an international competition to predict the structure of proteins,
which are close to being solved experimentally.
A prototype of the alignment tool ToPLign, including the fast threading
method 123D and the RDP method, has been distributed since mid 1994 and
been updated since then. The software is also available via the World Wide
Web and mirrored at the National Cancer Institute (NCI/NIH) in Frederick,
MD, USA. It is in use in various university institutes and some US biotechnology
companies.
Please contact:
Heinz Mevissen - GMD
Tel: +49 2241 14 2784
E-mail: heinz-theodor.mevissen@gmd.de
Joachim Selbig - GMD
Tel: +49 2241 14 2792
E-mail: joachim.selbig@gmd.de
Ralf Thiele - GMD
Tel: +49 2241 14 2302
E-mail: ralf.thiele@gmd.de
Ralf Zimmer - GMD
Tel: +49 2241 14 2818
E-mail: ralf.zimmer@gmd.de
Thomas Lengauer - GMD
Tel: +49 2241 14 2777
E-mail: thomas.lengauer@gmd.de
