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Energetics and mechanism of the normal-to-amyloidogenic isomerization of ?2-microglobulin: on-the-fly string method calculations.

ABSTRACT: We use on-the-fly finite temperature string method in collective variables to study the transition from a normal to an amyloidogenic conformation of ?2-microglobulin. We show that the protonation state of two histidine residues is of key importance and that under acidic (protonating) conditions, the transition to the amyloidgenic form is facilitated by both displacement of N-terminal residues to disrupt a hydrophobic pocket and by side-chain/side-chain electrostatic attraction, both of which facilitate a cis-trans prolyl isomerization. The free energy barriers for the normal-to-amyloidogenic isomerization are found to be 14.9 and 7.1 kcal/mol for the neutral and protonated cases, respectively, consistent with enhanced amyloidgenesis at low pH observed both in vitro and in hemodialysis-associated amyloidosis, and somewhat lower than experimentally determined barriers for bare prolyl cis-trans isomerization. We suggest specific mutagenesis experiments which could be used to further validate the mechanism observed.

SUBMITTER: Stober ST

PROVIDER: S-EPMC3437544 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations.

Stober Spencer T ST Abrams Cameron F CF

The journal of physical chemistry. B 20120731 31

We use on-the-fly finite temperature string method in collective variables to study the transition from a normal to an amyloidogenic conformation of β2-microglobulin. We show that the protonation state of two histidine residues is of key importance and that under acidic (protonating) conditions, the transition to the amyloidgenic form is facilitated by both displacement of N-terminal residues to disrupt a hydrophobic pocket and by side-chain/side-chain electrostatic attraction, both of which fac ...[more]

PMID: 22793795

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Project description:The dark-colored viologen radical cations are unstable in air and easily fade, thus greatly limiting their applications. If a suitable substituent is introduced into the structure, it will have the dual function of chromism and luminescence, which will broaden its application field. Here, Vio1·2Cl and Vio2·2Br were synthesized by introducing aromatic acetophenone and naphthophenone substituents into the viologen structure. The keto group (-CH2CO-) on the substituents is prone to isomerize into the enol structure (-CH[double bond, length as m-dash]COH-) in organic solvents, especially in DMSO, resulting in a larger conjugated system to stabilize the molecular structure and enhance fluorescence. The time-dependent fluorescence spectrum shows obvious keto-to-enol isomerization-induced fluorescence enhancement. The quantum yield also increased significantly (T = 1 day, ΦVio1 = 25.81%, ΦVio2 = 41.44%; T = 7 days, ΦVio1 = 31.48%, and ΦVio2 = 54.40%) in DMSO. The NMR and ESI-MS data at different times further confirmed that the fluorescence enhancement was caused by isomerization, and no other fluorescent impurities were produced in solution. DFT calculations show that the enol form is almost coplanar throughout the molecular structure, which is conducive to stabilizing the structure and enhancing fluorescence. The fluorescence emission peaks of the keto and enol structures of Vio12+ and Vio22+ were at 416-417 nm and 563-582 nm, respectively. The fluorescence relative oscillator strength of Vio12+ and Vio22+ enol structures is significantly higher than that of keto structures (f value changes from 1.53 to 2.63 for Vio12+ and from 1.62 to 2.81 for Vio22+), indicating stronger fluorescence emission of the enol structure. The calculated results are in good agreement with the experimental results. Vio1·2Cl and Vio2·2Br are the first examples of isomerization-induced fluorescence enhancement of viologen derivatives, which shows strong solvatofluorochromism under UV light, making up for the disadvantage that it is easy for a viologen radical to fade in air, and providing a new strategy for designing and synthesizing viologen materials with strong fluorescence.

Dataset Information

Energetics and mechanism of the normal-to-amyloidogenic isomerization of ?2-microglobulin: on-the-fly string method calculations.

Publications

Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations.

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