420 research outputs found
Using 3D Hidden Markov Models that explicitly represent spatial coordinates to model and compare protein structures
BACKGROUND: Hidden Markov Models (HMMs) have proven very useful in computational biology for such applications as sequence pattern matching, gene-finding, and structure prediction. Thus far, however, they have been confined to representing 1D sequence (or the aspects of structure that could be represented by character strings). RESULTS: We develop an HMM formalism that explicitly uses 3D coordinates in its match states. The match states are modeled by 3D Gaussian distributions centered on the mean coordinate position of each alpha carbon in a large structural alignment. The transition probabilities depend on the spread of the neighboring match states and on the number of gaps found in the structural alignment. We also develop methods for aligning query structures against 3D HMMs and scoring the result probabilistically. For 1D HMMs these tasks are accomplished by the Viterbi and forward algorithms. However, these will not work in unmodified form for the 3D problem, due to non-local quality of structural alignment, so we develop extensions of these algorithms for the 3D case. Several applications of 3D HMMs for protein structure classification are reported. A good separation of scores for different fold families suggests that the described construct is quite useful for protein structure analysis. CONCLUSION: We have created a rigorous 3D HMM representation for protein structures and implemented a complete set of routines for building 3D HMMs in C and Perl. The code is freely available from , and at this site we also have a simple prototype server to demonstrate the features of the described approach
kLog: A Language for Logical and Relational Learning with Kernels
We introduce kLog, a novel approach to statistical relational learning.
Unlike standard approaches, kLog does not represent a probability distribution
directly. It is rather a language to perform kernel-based learning on
expressive logical and relational representations. kLog allows users to specify
learning problems declaratively. It builds on simple but powerful concepts:
learning from interpretations, entity/relationship data modeling, logic
programming, and deductive databases. Access by the kernel to the rich
representation is mediated by a technique we call graphicalization: the
relational representation is first transformed into a graph --- in particular,
a grounded entity/relationship diagram. Subsequently, a choice of graph kernel
defines the feature space. kLog supports mixed numerical and symbolic data, as
well as background knowledge in the form of Prolog or Datalog programs as in
inductive logic programming systems. The kLog framework can be applied to
tackle the same range of tasks that has made statistical relational learning so
popular, including classification, regression, multitask learning, and
collective classification. We also report about empirical comparisons, showing
that kLog can be either more accurate, or much faster at the same level of
accuracy, than Tilde and Alchemy. kLog is GPLv3 licensed and is available at
http://klog.dinfo.unifi.it along with tutorials
Logical Hidden Markov Models
Logical hidden Markov models (LOHMMs) upgrade traditional hidden Markov
models to deal with sequences of structured symbols in the form of logical
atoms, rather than flat characters.
This note formally introduces LOHMMs and presents solutions to the three
central inference problems for LOHMMs: evaluation, most likely hidden state
sequence and parameter estimation. The resulting representation and algorithms
are experimentally evaluated on problems from the domain of bioinformatics
Representing Conversations for Scalable Overhearing
Open distributed multi-agent systems are gaining interest in the academic
community and in industry. In such open settings, agents are often coordinated
using standardized agent conversation protocols. The representation of such
protocols (for analysis, validation, monitoring, etc) is an important aspect of
multi-agent applications. Recently, Petri nets have been shown to be an
interesting approach to such representation, and radically different approaches
using Petri nets have been proposed. However, their relative strengths and
weaknesses have not been examined. Moreover, their scalability and suitability
for different tasks have not been addressed. This paper addresses both these
challenges. First, we analyze existing Petri net representations in terms of
their scalability and appropriateness for overhearing, an important task in
monitoring open multi-agent systems. Then, building on the insights gained, we
introduce a novel representation using Colored Petri nets that explicitly
represent legal joint conversation states and messages. This representation
approach offers significant improvements in scalability and is particularly
suitable for overhearing. Furthermore, we show that this new representation
offers a comprehensive coverage of all conversation features of FIPA
conversation standards. We also present a procedure for transforming AUML
conversation protocol diagrams (a standard human-readable representation), to
our Colored Petri net representation
Bayesian machine learning methods for predicting protein-peptide interactions and detecting mosaic structures in DNA sequences alignments
Short well-defined domains known as peptide recognition modules (PRMs) regulate many important protein-protein interactions involved in the formation of macromolecular complexes
and biochemical pathways. High-throughput experiments like yeast two-hybrid and phage
display are expensive and intrinsically noisy, therefore it would be desirable to target informative interactions and pursue in silico approaches. We propose a probabilistic discriminative
approach for predicting PRM-mediated protein-protein interactions from sequence data. The
model suffered from over-fitting, so Laplacian regularisation was found to be important in
achieving a reasonable generalisation performance. A hybrid approach yielded the best performance, where the binding site motifs were initialised with the predictions of a generative
model. We also propose another discriminative model which can be applied to all sequences
present in the organism at a significantly lower computational cost. This is due to its additional
assumption that the underlying binding sites tend to be similar.It is difficult to distinguish between the binding site motifs of the PRM due to the small
number of instances of each binding site motif. However, closely related species are expected
to share similar binding sites, which would be expected to be highly conserved. We investigated
rate variation along DNA sequence alignments, modelling confounding effects such as recombination. Traditional approaches to phylogenetic inference assume that a single phylogenetic
tree can represent the relationships and divergences between the taxa. However, taxa sequences
exhibit varying levels of conservation, e.g. due to regulatory elements and active binding sites,
and certain bacteria and viruses undergo interspecific recombination. We propose a phylogenetic factorial hidden Markov model to infer recombination and rate variation. We examined
the performance of our model and inference scheme on various synthetic alignments, and compared it to state of the art breakpoint models. We investigated three DNA sequence alignments:
one of maize actin genes, one bacterial (Neisseria), and the other of HIV-1. Inference is carried
out in the Bayesian framework, using Reversible Jump Markov Chain Monte Carlo
Computational Approaches to Drug Profiling and Drug-Protein Interactions
Despite substantial increases in R&D spending within the pharmaceutical industry, denovo drug design has become a time-consuming endeavour. High attrition rates led to a
long period of stagnation in drug approvals. Due to the extreme costs associated with
introducing a drug to the market, locating and understanding the reasons for clinical failure
is key to future productivity. As part of this PhD, three main contributions were made in
this respect. First, the web platform, LigNFam enables users to interactively explore
similarity relationships between ‘drug like’ molecules and the proteins they bind. Secondly,
two deep-learning-based binding site comparison tools were developed, competing with
the state-of-the-art over benchmark datasets. The models have the ability to predict offtarget interactions and potential candidates for target-based drug repurposing. Finally, the
open-source ScaffoldGraph software was presented for the analysis of hierarchical scaffold
relationships and has already been used in multiple projects, including integration into a
virtual screening pipeline to increase the tractability of ultra-large screening experiments.
Together, and with existing tools, the contributions made will aid in the understanding of
drug-protein relationships, particularly in the fields of off-target prediction and drug
repurposing, helping to design better drugs faster
A structural classification of protein-protein interactions for detection of convergently evolved motifs and for prediction of protein binding sites on sequence level
BACKGROUND: A long-standing challenge in the post-genomic era of Bioinformatics is the prediction of protein-protein interactions, and ultimately the prediction of protein functions. The problem is intrinsically harder, when only amino acid sequences are available, but a solution is more universally applicable. So far, the problem of uncovering protein-protein interactions has been addressed in a variety of ways, both experimentally and computationally. MOTIVATION: The central problem is: How can protein complexes with solved threedimensional structure be utilized to identify and classify protein binding sites and how can knowledge be inferred from this classification such that protein interactions can be predicted for proteins without solved structure? The underlying hypothesis is that protein binding sites are often restricted to a small number of residues, which additionally often are well-conserved in order to maintain an interaction. Therefore, the signal-to-noise ratio in binding sites is expected to be higher than in other parts of the surface. This enables binding site detection in unknown proteins, when homology based annotation transfer fails. APPROACH: The problem is addressed by first investigating how geometrical aspects of domain-domain associations can lead to a rigorous structural classification of the multitude of protein interface types. The interface types are explored with respect to two aspects: First, how do interface types with one-sided homology reveal convergently evolved motifs? Second, how can sequential descriptors for local structural features be derived from the interface type classification? Then, the use of sequential representations for binding sites in order to predict protein interactions is investigated. The underlying algorithms are based on machine learning techniques, in particular Hidden Markov Models. RESULTS: This work includes a novel approach to a comprehensive geometrical classification of domain interfaces. Alternative structural domain associations are found for 40% of all family-family interactions. Evaluation of the classification algorithm on a hand-curated set of interfaces yielded a precision of 83% and a recall of 95%. For the first time, a systematic screen of convergently evolved motifs in 102.000 protein-protein interactions with structural information is derived. With respect to this dataset, all cases related to viral mimicry of human interface bindings are identified. Finally, a library of 740 motif descriptors for binding site recognition - encoded as Hidden Markov Models - is generated and cross-validated. Tests for the significance of motifs are provided. The usefulness of descriptors for protein-ligand binding sites is demonstrated for the case of "ATP-binding", where a precision of 89% is achieved, thus outperforming comparable motifs from PROSITE. In particular, a novel descriptor for a P-loop variant has been used to identify ATP-binding sites in 60 protein sequences that have not been annotated before by existing motif databases
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