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Dynamic properties of pH-dependent structural organization of the amyloidogenic beta-protein (1-40).

ABSTRACT: The structural organization of the amyloidogenic beta-protein containing 40 amino acid residues (Abeta40) was studied by the high temperature molecular dynamics simulations in the acidic (pH approximately 3) and basic (pH approximately 8) pH regions. The obtained data suggest that the central Ala21-Gly29 segment of Abeta40 can adopt folded and partially unfolded structures. At the basic pH, this segment forms folded structures stabilized by electrostatic interactions and hydrogen bonds. At the acidic pH, it forms partially unfolded structures. Two other segments flanking to the central segment exhibit the propensity to adopt unstable interconverting alpha-helical, 3(10)-helical and turn-like structures. One of these segments is comprised of the Ala30-Val36 residues at both of the considered pHs. The second segment is comprised of the Glu11-Phe20 at the basic pH and of the Glu11-Val24 residues at the acidic pHs. The revealed pH-dependent structuration of the Abeta40 allowed us to suggest a possible scenario for initial Abeta aggregation. According to this scenario, the occurrence of the partially unfolded states of the Ala21-Gly29 segment plays main role in the Abeta oligomerization process.

SUBMITTER: Rubinstein A

PROVIDER: S-EPMC2676741 | biostudies-literature | 2009 Jan-Mar

REPOSITORIES: biostudies-literature

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Dynamic properties of pH-dependent structural organization of the amyloidogenic beta-protein (1-40).

Rubinstein Alexander A Lyubchenko Yuri L YL Sherman Simon S

Prion 20090110 1

The structural organization of the amyloidogenic beta-protein containing 40 amino acid residues (Abeta40) was studied by the high temperature molecular dynamics simulations in the acidic (pH approximately 3) and basic (pH approximately 8) pH regions. The obtained data suggest that the central Ala21-Gly29 segment of Abeta40 can adopt folded and partially unfolded structures. At the basic pH, this segment forms folded structures stabilized by electrostatic interactions and hydrogen bonds. At the a ...[more]

PMID: 19372746

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Project description:A recently engineered mutant of cyan fluorescent protein (WasCFP) that exhibits pH-dependent absorption suggests that its tryptophan-based chromophore switches between neutral (protonated) and charged (deprotonated) states depending on external pH. At pH 8.1, the latter gives rise to green fluorescence as opposed to the cyan color of emission that is characteristic for the neutral form at low pH. Given the high energy cost of deprotonating the tryptophan at the indole nitrogen, this behavior is puzzling, even if the stabilizing effect of the V61K mutation in proximity to the protonation/deprotonation site is considered. Because of its potential to open new avenues for the development of optical sensors and photoconvertible fluorescent proteins, a mechanistic understanding of how the charged state in WasCFP can possibly be stabilized is thus important. Attributed to the dynamic nature of proteins, such understanding often requires knowledge of the various conformations adopted, including transiently populated conformational states. Transient conformational states triggered by pH are of emerging interest and have been shown to be important whenever ionizable groups interact with hydrophobic environments. Using a combination of the weighted-ensemble sampling method and explicit-solvent constant pH molecular dynamics (CPHMD(MS?D)) simulations, we have identified a solvated transient state, characterized by a partially open ?-barrel where the chromophore pKa of 6.8 is shifted by over 20 units from that of the closed form (6.8 and 31.7, respectively). This state contributes a small population at low pH (12% at pH 6.1) but becomes dominant at mildly basic conditions, contributing as much as 53% at pH 8.1. This pH-dependent population shift between neutral (at pH 6.1) and charged (at pH 8.1) forms is thus responsible for the observed absorption behavior of WasCFP. Our findings demonstrate the conditions necessary to stabilize the charged state of the WasCFP chromophore (namely, local solvation at the deprotonation site and a partial flexibility of the protein ?-barrel structure) and provide the first evidence that transient conformational states can control optical properties of fluorescent proteins.

Dataset Information

Dynamic properties of pH-dependent structural organization of the amyloidogenic beta-protein (1-40).

Publications

Dynamic properties of pH-dependent structural organization of the amyloidogenic beta-protein (1-40).

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