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Order in Disorder as Observed by the "Hydrophobic Cluster Analysis" of Protein Sequences.

ABSTRACT: Hydrophobic cluster analysis (HCA) is an original approach for protein sequence analysis, which provides access to the foldable repertoire of the protein universe, including yet unannotated protein segments ("dark proteome"). Foldable segments correspond to ordered regions, as well as to intrinsically disordered regions (IDRs) undergoing disorder to order transitions. In this review, how HCA can be used to give insight into this last category of foldable segments is illustrated, with examples matching known 3D structures. After reviewing the HCA principles, examples of short foldable segments are given, which often contain short linear motifs, typically matching hydrophobic clusters. These segments become ordered upon contact with partners, with secondary structure preferences generally corresponding to those observed in the 3D structures within the complexes. Such small foldable segments are sometimes larger than the segments of known 3D structures, including flanking hydrophobic clusters that may be critical for interaction specificity or regulation, as well as intervening sequences allowing fuzziness. Cases of larger conditionally disordered domains are also presented, with lower density in hydrophobic clusters than well-folded globular domains or with exposed hydrophobic patches, which are stabilized by interaction with partners.

SUBMITTER: Bitard-Feildel T

PROVIDER: S-EPMC7168002 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Order in Disorder as Observed by the "Hydrophobic Cluster Analysis" of Protein Sequences.

Bitard-Feildel Tristan T Lamiable Alexis A Mornon Jean-Paul JP Callebaut Isabelle I

Proteomics 20181030 21-22

Hydrophobic cluster analysis (HCA) is an original approach for protein sequence analysis, which provides access to the foldable repertoire of the protein universe, including yet unannotated protein segments ("dark proteome"). Foldable segments correspond to ordered regions, as well as to intrinsically disordered regions (IDRs) undergoing disorder to order transitions. In this review, how HCA can be used to give insight into this last category of foldable segments is illustrated, with examples ma ...[more]

PMID: 30299594

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Project description:BackgroundHydrophobic Cluster Analysis (HCA) is an efficient way to compare highly divergent sequences through the implicit secondary structure information directly derived from hydrophobic clusters. However, its efficiency and application are currently limited by the need of user expertise. In order to help the analysis of HCA plots, we report here the structural preferences of hydrophobic cluster species, which are frequently encountered in globular domains of proteins. These species are characterized only by their hydrophobic/non-hydrophobic dichotomy. This analysis has been extended to loop-forming clusters, using an appropriate loop alphabet.ResultsThe structural behavior of hydrophobic cluster species, which are typical of protein globular domains, was investigated within banks of experimental structures, considered at different levels of sequence redundancy. The 294 more frequent hydrophobic cluster species were analyzed with regard to their association with the different secondary structures (frequencies of association with secondary structures and secondary structure propensities). Hydrophobic cluster species are predominantly associated with regular secondary structures, and a large part (60 %) reveals preferences for alpha-helices or beta-strands. Moreover, the analysis of the hydrophobic cluster amino acid composition generally allows for finer prediction of the regular secondary structure associated with the considered cluster within a cluster species. We also investigated the behavior of loop forming clusters, using a "PGDNS" alphabet. These loop clusters do not overlap with hydrophobic clusters and are highly associated with coils. Finally, the structural information contained in the hydrophobic structural words, as deduced from experimental structures, was compared to the PSI-PRED predictions, revealing that beta-strands and especially alpha-helices are generally over-predicted within the limits of typical beta and alpha hydrophobic clusters.ConclusionThe dictionary of hydrophobic clusters described here can help the HCA user to interpret and compare the HCA plots of globular protein sequences, as well as provides an original fundamental insight into the structural bricks of protein folds. Moreover, the novel loop cluster analysis brings additional information for secondary structure prediction on the whole sequence through a generalized cluster analysis (GCA), and not only on regular secondary structures. Such information lays the foundations for developing a new and original tool for secondary structure prediction.

Project description:Theory and computer simulation studies have predicted that water molecules around hydrophobic molecules should undergo an order-disorder transition with increasing solute size around a 1 nm length scale. Some theories predict the formation of a clathrate-like ordered structure around smaller hydrophobic solutes (<1 nm) and the formation of disordered vapor-liquid interfaces around larger solutes (>1 nm) and surfaces. Experimental validation of these predictions has often been elusive and contradictory. High-resolution Raman spectroscopy has detected that water around small hydrophobic solutes shows a signature similar to that of bulk water at lower temperature (increased ordering and a stronger hydrogen-bonded network). Similarly, water around larger solutes shows an increasing population of dangling OH bonds very similar to higher temperature bulk water. Thus, the solute size dependence of the structure and dynamics of water around hydrophobic molecules seems to have an analogy with the temperature dependence in bulk water. In this work, using atomistic classical molecular dynamics (MD) simulations, we have systematically investigated this aspect and characterized this interesting analogy. Structural order parameters including the tetrahedral order parameter (Q), hydrogen bond distribution, and vibrational power spectrum highlight this similarity. However, in contrast to the experimental observations, we do not observe any length-dependent crossover for linear hydrophobic alcohols (n-alkanols) using classical MD simulations. This is in agreement with earlier findings that linear alkane chains do not demonstrate the length-dependent order-disorder transition due to the presence of a sub-nanometer length scale along the cross section of the chain. Moreover, the collapsed state of linear hydrocarbon chains is not significantly populated for smaller chains (number of carbons below 20). In the context of our computational results, we raise several pertinent questions related to the sensitivity of various structural and dynamical parameters toward capturing these complex phenomena of hydrophobic hydration.

Dataset Information

Order in Disorder as Observed by the "Hydrophobic Cluster Analysis" of Protein Sequences.

Publications

Order in Disorder as Observed by the "Hydrophobic Cluster Analysis" of Protein Sequences.

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