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BITS2007 Meeting
BITS2007 Meeting



26-28 April 2007 Napoli, Italy

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Critical Assessment of Side Chain Prediction (CASCP): an in-house evaluation on single-point mutants of lysozyme.
 
Motivation
The simulation of protein structure by computational methods
has been exceptionally
improved during the last 15 years, as proved by the results
from CASP (Critical
Assessment of techniques for protein Structure Prediction)
competition. However, the
prediction of the correct conformation of side chains is
still a major problem.
Several programs are available and are widely used to place
the side chains on the
backbone of a protein structure and to optimize their
conformations; however, serious
questions can be made on the correctness of their
predictions. The scope of the
present work is to assess the ability of three widely used
and freely available
programs for side chain conformation prediction (NCN, SCAP
and SCWRL) to simulate the
introduction of a single point mutation in a structure and
the effects of this
mutation on the structure itself.

Methods
We chose as a benchmark the phage T4 lysozyme, for which
hundreds of single point
mutant structures are present in the PDB database. Starting
from the structures of
the wild type and of the "pseudo-wild-type" lysozyme (in
which two cysteine residues
are mutated to an alanine and a threonine residue), we
introduced different single
point mutations (for pseudo-wild-type, in addition to the
two mutant residues already
present), and we optimized the side chain conformations of
the mutants with each of
the three programs. The resulting structures were compared
with the corresponding
structures available in PDB using the traditional parameters
adopted for this kind of
evaluation, i.e. by analyzing the overall and average RMSD,
with or without the
inclusion of Cbeta atom in calculations, and the differences
in chi1 and chi1+2
angles on the side chains.

Results
The results for the predictions on this benchmark appear to
be worse than those
calculated by the Authors on their benchmarks and published
in the papers related to
each method. The program NCN appears to be the most accurate
for this benchmark both
in terms of angle accuracy and RMSD, but in general it
predicts no more than 70% of
chi1 and chi1+2 dihedrals correctly (the prediction was
considered correct for a
dihedral angle when the deviation between the predicted and
the experimental value
was less than 20). The overall RMSD is 1.90 A when Cbeta
atom is not included, 1.68
A when it is included in calculations. The programs SCAP and
SCWRL perform generally
worse than NCN both in terms of dihedral angle predictions
and RMSD. SCWRL performs
slightly better than SCAP in terms of dihedral angle
predictions, the opposite is
true for RMSD.
We also decomposed our results in terms of side chain
exposure to solvent, polarity,
size of mutations and influence on the nearest residues to
the mutations. We found
that generally side chains conformations are better
predicted in core residues (with
less than 10% solvent accessible area of the side-chain)
than in the exposed ones,
and the accuracy of prediction is similar for residues near
the mutation or far from
the site of mutation. The accuracy of prediction is higher
when the size of mutant
side chain is conserved, and a large to small mutation is
better simulated than the
opposite. Instead, the polarity of mutation affects the
prediction of side chain
conformation to a lesser extent.
This study confirms the need for better predictions of side
chains conformations;
however it also confirms that programs which are
parameterized by taking into account
not only a large rotamer library but also potential energy
functions perform better,
although they need a higher amount of computational time.
 
Id: 102
Place: Napoli, Italy
Centro Congressi "Federico II"
Via Partenope 36
Napoli
Starting date:
26-Apr-2007   18:20
Duration: 20'
Contribution type: Oral
Primary Authors: MARABOTTI, Anna (Laboratory of Bioinformatics, Institute of Food Science, CNR, Avellino)
Co-Authors: FACCHIANO, Angelo (Laboratory of Bioinformatics, Institute of Food Science, CNR, Avellino)
Presenters: MARABOTTI, Anna
 
Included in session: Session 2: Novel methodologies, algorithms and tools
Included in track: Novel methodologies, algorithms and tools
 




bits2007_support@ceinge.unina.it | Last modified 08 July 2009 10:35 |




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