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?-Bulges: extensive structural analyses of ?-sheets irregularities.

ABSTRACT: ?-Sheets are quite frequent in protein structures and are stabilized by regular main-chain hydrogen bond patterns. Irregularities in ?-sheets, named ?-bulges, are distorted regions between two consecutive hydrogen bonds. They disrupt the classical alternation of side chain direction and can alter the directionality of ?-strands. They are implicated in protein-protein interactions and are introduced to avoid ?-strand aggregation. Five different types of ?-bulges are defined. Previous studies on ?-bulges were performed on a limited number of protein structures or one specific family. These studies evoked a potential conservation during evolution. In this work, we analyze the ?-bulge distribution and conservation in terms of local backbone conformations and amino acid composition. Our dataset consists of 66 times more ?-bulges than the last systematic study (Chan et al. Protein Science 1993, 2:1574-1590). Novel amino acid preferences are underlined and local structure conformations are highlighted by the use of a structural alphabet. We observed that ?-bulges are preferably localized at the N- and C-termini of ?-strands, but contrary to the earlier studies, no significant conservation of ?-bulges was observed among structural homologues. Displacement of ?-bulges along the sequence was also investigated by Molecular Dynamics simulations.

SUBMITTER: Craveur P

PROVIDER: S-EPMC3795495 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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β-Bulges: extensive structural analyses of β-sheets irregularities.

Craveur Pierrick P Joseph Agnel Praveen AP Rebehmed Joseph J de Brevern Alexandre G AG

Protein science : a publication of the Protein Society 20130914 10

β-Sheets are quite frequent in protein structures and are stabilized by regular main-chain hydrogen bond patterns. Irregularities in β-sheets, named β-bulges, are distorted regions between two consecutive hydrogen bonds. They disrupt the classical alternation of side chain direction and can alter the directionality of β-strands. They are implicated in protein-protein interactions and are introduced to avoid β-strand aggregation. Five different types of β-bulges are defined. Previous studies on β ...[more]

PMID: 23904395

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Project description:The Dengue has become a global public health threat, with over 100 million infections annually; to date there is no specific vaccine or any antiviral drug. The structures of the envelope (E) proteins of the four known serotype of the dengue virus (DENV) are already known, but there are insufficient molecular details of their structural behavior in solution in the distinct environmental conditions in which the DENVs are submitted, from the digestive tract of the mosquito up to its replication inside the host cell. Such detailed knowledge becomes important because of the multifunctional character of the E protein: it mediates the early events in cell entry, via receptor endocytosis and, as a class II protein, participates determinately in the process of membrane fusion. The proposed infection mechanism asserts that once in the endosome, at low pH, the E homodimers dissociate and insert into the endosomal lipid membrane, after an extensive conformational change, mainly on the relative arrangement of its three domains. In this work we employ all-atom explicit solvent Molecular Dynamics simulations to specify the thermodynamic conditions in that the E proteins are induced to experience extensive structural changes, such as during the process of reducing pH. We study the structural behavior of the E protein monomer at acid pH solution of distinct ionic strength. Extensive simulations are carried out with all the histidine residues in its full protonated form at four distinct ionic strengths. The results are analyzed in detail from structural and energetic perspectives, and the virtual protein movements are described by means of the principal component analyses. As the main result, we found that at acid pH and physiological ionic strength, the E protein suffers a major structural change; for lower or higher ionic strengths, the crystal structure is essentially maintained along of all extensive simulations. On the other hand, at basic pH, when all histidine residues are in the unprotonated form, the protein structure is very stable for ionic strengths ranging from 0 to 225 mM. Therefore, our findings support the hypothesis that the histidines constitute the hot points that induce configurational changes of E protein in acid pH, and give extra motivation to the development of new ideas for antivirus compound design.

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?-Bulges: extensive structural analyses of ?-sheets irregularities.

Publications

β-Bulges: extensive structural analyses of β-sheets irregularities.

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