10,129 research outputs found
Deriving a mutation index of carcinogenicity using protein structure and protein interfaces
With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/
Toward a multilevel representation of protein molecules: comparative approaches to the aggregation/folding propensity problem
This paper builds upon the fundamental work of Niwa et al. [34], which
provides the unique possibility to analyze the relative aggregation/folding
propensity of the elements of the entire Escherichia coli (E. coli) proteome in
a cell-free standardized microenvironment. The hardness of the problem comes
from the superposition between the driving forces of intra- and inter-molecule
interactions and it is mirrored by the evidences of shift from folding to
aggregation phenotypes by single-point mutations [10]. Here we apply several
state-of-the-art classification methods coming from the field of structural
pattern recognition, with the aim to compare different representations of the
same proteins gathered from the Niwa et al. data base; such representations
include sequences and labeled (contact) graphs enriched with chemico-physical
attributes. By this comparison, we are able to identify also some interesting
general properties of proteins. Notably, (i) we suggest a threshold around 250
residues discriminating "easily foldable" from "hardly foldable" molecules
consistent with other independent experiments, and (ii) we highlight the
relevance of contact graph spectra for folding behavior discrimination and
characterization of the E. coli solubility data. The soundness of the
experimental results presented in this paper is proved by the statistically
relevant relationships discovered among the chemico-physical description of
proteins and the developed cost matrix of substitution used in the various
discrimination systems.Comment: 17 pages, 3 figures, 46 reference
A methodology for determining amino-acid substitution matrices from set covers
We introduce a new methodology for the determination of amino-acid
substitution matrices for use in the alignment of proteins. The new methodology
is based on a pre-existing set cover on the set of residues and on the
undirected graph that describes residue exchangeability given the set cover.
For fixed functional forms indicating how to obtain edge weights from the set
cover and, after that, substitution-matrix elements from weighted distances on
the graph, the resulting substitution matrix can be checked for performance
against some known set of reference alignments and for given gap costs. Finding
the appropriate functional forms and gap costs can then be formulated as an
optimization problem that seeks to maximize the performance of the substitution
matrix on the reference alignment set. We give computational results on the
BAliBASE suite using a genetic algorithm for optimization. Our results indicate
that it is possible to obtain substitution matrices whose performance is either
comparable to or surpasses that of several others, depending on the particular
scenario under consideration
Pairwise alignment incorporating dipeptide covariation
Motivation: Standard algorithms for pairwise protein sequence alignment make
the simplifying assumption that amino acid substitutions at neighboring sites
are uncorrelated. This assumption allows implementation of fast algorithms for
pairwise sequence alignment, but it ignores information that could conceivably
increase the power of remote homolog detection. We examine the validity of this
assumption by constructing extended substitution matrixes that encapsulate the
observed correlations between neighboring sites, by developing an efficient and
rigorous algorithm for pairwise protein sequence alignment that incorporates
these local substitution correlations, and by assessing the ability of this
algorithm to detect remote homologies. Results: Our analysis indicates that
local correlations between substitutions are not strong on the average.
Furthermore, incorporating local substitution correlations into pairwise
alignment did not lead to a statistically significant improvement in remote
homology detection. Therefore, the standard assumption that individual residues
within protein sequences evolve independently of neighboring positions appears
to be an efficient and appropriate approximation
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