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Orientation of tyrosine side chain in neurotoxic A? differs in two different secondary structures of the peptide.

ABSTRACT: Amyloid ? (A?) peptide is present as a major component in amyloid plaque that is one of the hallmarks of Alzheimer's disease. The peptide contains a single tyrosine residue and A? has a major implication in the pathology of the disease progression. Current investigation revealed that the tyrosine side chain attained two different critical stereo orientations in two dissimilar conformational states of the peptide. The extended ?-helical structure of the peptide observed in an apolar solvent or methanol/water mixture became disordered in aqueous medium and the radius of gyration decreased. In aqueous medium, the torsional angle around C?-C? of tyrosine group became -60°. However, in its ?-helical conformation in an apolar system, the measured angle was 180° and this rotameric state may be reasoned behind stronger tyrosine fluorescence compared with the disordered state of the peptide. Molecular dynamics simulation analyses and spectroscopic studies have helped us to understand the major structural changes in the secondary structure of the peptide in the two conformational states. A conformational clustering indicated that the compact state is more stable with tyrosine residue attaining the torsion angle value of -60°, whereas the native state (in HFIP/water mixture) is prevalent at a torsion angle value of -180°. High solvent accessibility has possibly stabilized the particular rotameric state (-60°) of the tyrosine residue and could be the reason behind decrease in fluorescence of the sole tyrosine residue in an aqueous buffer solution (pH 7.4) compared with its fluorescence in the ?-helical structure in the micellar environment.

SUBMITTER: Das S

PROVIDER: S-EPMC5098961 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Orientation of tyrosine side chain in neurotoxic Aβ differs in two different secondary structures of the peptide.

Das Swagata S Das Supriya S Roy Anupam A Pal Uttam U Maiti Nakul C NC

Royal Society open science 20161005 10

Amyloid β (Aβ) peptide is present as a major component in amyloid plaque that is one of the hallmarks of Alzheimer's disease. The peptide contains a single tyrosine residue and Aβ has a major implication in the pathology of the disease progression. Current investigation revealed that the tyrosine side chain attained two different critical stereo orientations in two dissimilar conformational states of the peptide. The extended α-helical structure of the peptide observed in an apolar solvent or me ...[more]

PMID: 27853536

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Project description:Protein structure modeling and prediction have important applications throughout the biological sciences, from the design of pharmaceuticals to the elucidation of enzyme mechanisms. At the core of most protein modeling is an energy function, the minimum of which represents the free energy "cost" for forming a correct protein structure. The most commonly used energy functions are knowledge-based statistical potential functions; that is, they are empirically derived from statistical analysis of a set of high-resolution protein structures. When that kind of potential function is constructed, the anisotropic orientation dependence between the interacting groups is a critical component for accurately representing key molecular interactions, such as those involved in protein side-chain packing. In the literature, however, many potential functions are limited in their ability to describe orientation dependence. In all-atom potentials, they typically ignore heterogeneous chemical-bond connectivity. In coarse-grained potentials, such as (semi)-residue-based potentials, the simplified representation of residues often reduces the sensitivity of the potential to side-chain orientation. Recently, in an effort to maximally capture the orientation dependence in side-chain interactions, a new type of all-atom statistical potential was developed: OPUS-PSP (potential derived from side-chain packing). The key feature of this potential is its explicit description of orientation dependence in molecular interactions, which is achieved with a basis set of 19 rigid-body blocks extracted from the chemical structures of 20 amino acid residues. This basis set is specifically designed to maximally capture the essential elements of orientation dependence in molecular packing interactions. The potential is constructed from the orientation-specific packing statistics of pairs of those blocks in a nonredundant structural database. On decoy set tests, OPUS-PSP significantly outperforms most of the existing knowledge-based potentials in terms of both its ability to recognize native structures and its consistency in achieving high Z scores across decoy sets. The application of OPUS-PSP to conformational modeling of side chains has led to another method, called OPUS-Rota. In terms of combined speed and accuracy, OPUS-Rota outperforms all of the other methods in modeling side-chain conformation. In this Account, we briefly outline the basic scheme of the OPUS-PSP potential and its application to side-chain modeling via OPUS-Rota. Future perspectives on the modeling of orientation dependence are also discussed. The computer programs for OPUS-PSP and OPUS-Rota can be downloaded at http://sigler.bioch.bcm.tmc.edu/MaLab . They are free for academic users.

Dataset Information

Orientation of tyrosine side chain in neurotoxic A? differs in two different secondary structures of the peptide.

Publications

Orientation of tyrosine side chain in neurotoxic Aβ differs in two different secondary structures of the peptide.

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