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Euclidean sections of protein conformation space and their implications in dimensionality reduction.

ABSTRACT: Dimensionality reduction is widely used in searching for the intrinsic reaction coordinates for protein conformational changes. We find the dimensionality-reduction methods using the pairwise root-mean-square deviation (RMSD) as the local distance metric face a challenge. We use Isomap as an example to illustrate the problem. We believe that there is an implied assumption for the dimensionality-reduction approaches that aim to preserve the geometric relations between the objects: both the original space and the reduced space have the same kind of geometry, such as Euclidean geometry vs. Euclidean geometry or spherical geometry vs. spherical geometry. When the protein free energy landscape is mapped onto a 2D plane or 3D space, the reduced space is Euclidean, thus the original space should also be Euclidean. For a protein with N atoms, its conformation space is a subset of the 3N-dimensional Euclidean space R(3N). We formally define the protein conformation space as the quotient space of R(3N) by the equivalence relation of rigid motions. Whether the quotient space is Euclidean or not depends on how it is parameterized. When the pairwise RMSD is employed as the local distance metric, implicit representations are used for the protein conformation space, leading to no direct correspondence to a Euclidean set. We have demonstrated that an explicit Euclidean-based representation of protein conformation space and the local distance metric associated to it improve the quality of dimensionality reduction in the tetra-peptide and ?-hairpin systems.

SUBMITTER: Duan M

PROVIDER: S-EPMC4177328 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Euclidean sections of protein conformation space and their implications in dimensionality reduction.

Duan Mojie M Li Minghai M Han Li L Huo Shuanghong S

Proteins 20140619 10

Dimensionality reduction is widely used in searching for the intrinsic reaction coordinates for protein conformational changes. We find the dimensionality-reduction methods using the pairwise root-mean-square deviation (RMSD) as the local distance metric face a challenge. We use Isomap as an example to illustrate the problem. We believe that there is an implied assumption for the dimensionality-reduction approaches that aim to preserve the geometric relations between the objects: both the origin ...[more]

PMID: 24913095

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Project description:BackgroundSystems wide modeling and analysis of signaling networks is essential for understanding complex cellular behaviors, such as the biphasic responses to different combinations of cytokines and growth factors. For example, tumor necrosis factor (TNF) can act as a proapoptotic or prosurvival factor depending on its concentration, the current state of signaling network and the presence of other cytokines. To understand combinatorial regulation in such systems, new computational approaches are required that can take into account non-linear interactions in signaling networks and provide tools for clustering, visualization and predictive modeling.ResultsHere we extended and applied an unsupervised non-linear dimensionality reduction approach, Isomap, to find clusters of similar treatment conditions in two cell signaling networks: (I) apoptosis signaling network in human epithelial cancer cells treated with different combinations of TNF, epidermal growth factor (EGF) and insulin and (II) combination of signal transduction pathways stimulated by 21 different ligands based on AfCS double ligand screen data. For the analysis of the apoptosis signaling network we used the Cytokine compendium dataset where activity and concentration of 19 intracellular signaling molecules were measured to characterise apoptotic response to TNF, EGF and insulin. By projecting the original 19-dimensional space of intracellular signals into a low-dimensional space, Isomap was able to reconstruct clusters corresponding to different cytokine treatments that were identified with graph-based clustering. In comparison, Principal Component Analysis (PCA) and Partial Least Squares - Discriminant analysis (PLS-DA) were unable to find biologically meaningful clusters. We also showed that by using Isomap components for supervised classification with k-nearest neighbor (k-NN) and quadratic discriminant analysis (QDA), apoptosis intensity can be predicted for different combinations of TNF, EGF and insulin. Prediction accuracy was highest when early activation time points in the apoptosis signaling network were used to predict apoptosis rates at later time points. Extended Isomap also outperformed PCA on the AfCS double ligand screen data. Isomap identified more functionally coherent clusters than PCA and captured more information in the first two-components. The Isomap projection performs slightly worse when more signaling networks are analyzed; suggesting that the mapping function between cues and responses becomes increasingly non-linear when large signaling pathways are considered.ConclusionWe developed and applied extended Isomap approach for the analysis of cell signaling networks. Potential biological applications of this method include characterization, visualization and clustering of different treatment conditions (i.e. low and high doses of TNF) in terms of changes in intracellular signaling they induce.

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Euclidean sections of protein conformation space and their implications in dimensionality reduction.

Publications

Euclidean sections of protein conformation space and their implications in dimensionality reduction.

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