Dataset Information

Ensemblator v3: Robust atom-level comparative analyses and classification of protein structure ensembles.

ABSTRACT: Ensembles of protein structures are increasingly used to represent the conformational variation of a protein as determined by experiment and/or by molecular simulations, as well as uncertainties that may be associated with structure determinations or predictions. Making the best use of such information requires the ability to quantitatively compare entire ensembles. For this reason, we recently introduced the Ensemblator (Clark et al., Protein Sci 2015; 24:1528), a novel approach to compare user-defined groups of models, in residue level detail. Here we describe Ensemblator v3, an open-source program that employs the same basic ensemble comparison strategy but includes major advances that make it more robust, powerful, and user-friendly. Ensemblator v3 carries out multiple sequence alignments to facilitate the generation of ensembles from non-identical input structures, automatically optimizes the key global overlay parameter, optionally performs "ensemble clustering" to classify the models into subgroups, and calculates a novel "discrimination index" that quantifies similarities and differences, at residue or atom level, between each pair of subgroups. The clustering and automatic options mean that no pre-knowledge about an ensemble is required for its analysis. After describing the novel features of Ensemblator v3, we demonstrate its utility using three case studies that illustrate the ease with which complex analyses are accomplished, and the kinds of insights derived from clustering into subgroups and from the detailed information that locates significant differences. The Ensemblator v3 enhances the structural biology toolbox by greatly expanding the kinds of problems to which this ensemble comparison strategy can be applied.

SUBMITTER: Brereton AE

PROVIDER: S-EPMC5734391 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Ensemblator v3: Robust atom-level comparative analyses and classification of protein structure ensembles.

Brereton Andrew E AE Karplus P Andrew PA

Protein science : a publication of the Protein Society 20170811 1

Ensembles of protein structures are increasingly used to represent the conformational variation of a protein as determined by experiment and/or by molecular simulations, as well as uncertainties that may be associated with structure determinations or predictions. Making the best use of such information requires the ability to quantitatively compare entire ensembles. For this reason, we recently introduced the Ensemblator (Clark et al., Protein Sci 2015; 24:1528), a novel approach to compare user ...[more]

PMID: 28762605

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Project description:A precise representation of the spatial distribution of hydrophobicity, hydrophilicity and charges on the molecular surface of proteins is critical for the understanding of the interaction with small molecules and larger systems. The representation of hydrophobicity is rarely done at atom-level, as this property is generally assigned to residues. A new methodology for the derivation of atomic hydrophobicity from any amino acid-based hydrophobicity scale was used to derive 8 sets of atomic hydrophobicities, one of which was used to generate the molecular surfaces for 35 proteins with convex structures, 5 of which, i.e., lysozyme, ribonuclease, hemoglobin, albumin and IgG, have been analyzed in more detail. Sets of the molecular surfaces of the model proteins have been constructed using spherical probes with increasingly large radii, from 1.4 to 20 Å, followed by the quantification of (i) the surface hydrophobicity; (ii) their respective molecular surface areas, i.e., total, hydrophilic and hydrophobic area; and (iii) their relative densities, i.e., divided by the total molecular area; or specific densities, i.e., divided by property-specific area. Compared with the amino acid-based formalism, the atom-level description reveals molecular surfaces which (i) present an approximately two times more hydrophilic areas; with (ii) less extended, but between 2 to 5 times more intense hydrophilic patches; and (iii) 3 to 20 times more extended hydrophobic areas. The hydrophobic areas are also approximately 2 times more hydrophobicity-intense. This, more pronounced "leopard skin"-like, design of the protein molecular surface has been confirmed by comparing the results for a restricted set of homologous proteins, i.e., hemoglobins diverging by only one residue (Trp37). These results suggest that the representation of hydrophobicity on the protein molecular surfaces at atom-level resolution, coupled with the probing of the molecular surface at different geometric resolutions, can capture processes that are otherwise obscured to the amino acid-based formalism.

Dataset Information

Ensemblator v3: Robust atom-level comparative analyses and classification of protein structure ensembles.

Publications

Ensemblator v3: Robust atom-level comparative analyses and classification of protein structure ensembles.

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