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Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of plaque deposits in the human brain. The main component of these plaques consists of highly ordered structures called amyloid fibrils, formed by the amyloid ?-peptide (A?). The mechanism connecting A? and AD is yet undetermined. In a previous study, a coarse-grained united-residue model and molecular dynamics simulations were used to model the growth mechanism of A? amyloid fibrils. On the basis of these simulations, a dock/lock mechanism was proposed, in which A? fibrils grow by adding monomers at either end of an amyloid fibril template. To examine the structures in the early time-scale formation and growth of amyloid fibrils, simulated two-dimensional ultraviolet spectroscopy is used. These early structures are monitored in the far ultraviolet regime (? = 190-250 nm) in which the computed signals originate from the backbone n?* and ??* transitions. These signals show distinct cross-peak patterns that can be used, in combination with molecular dynamics, to monitor local dynamics and conformational changes in the secondary structure of A?-peptides. The protein geometry-correlated chiral xxxy signal and the non-chiral combined signal xyxy-xyyx were found to be sensitive to, and in agreement with, a dock/lock pathway.

SUBMITTER: Lam AR

PROVIDER: S-EPMC3684205 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy.

Lam A R AR Rodriguez J J JJ Rojas A A Scheraga H A HA Mukamel S S

The journal of physical chemistry. A 20130107 2

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of plaque deposits in the human brain. The main component of these plaques consists of highly ordered structures called amyloid fibrils, formed by the amyloid β-peptide (Aβ). The mechanism connecting Aβ and AD is yet undetermined. In a previous study, a coarse-grained united-residue model and molecular dynamics simulations were used to model the growth mechanism of Aβ amyloid fibrils. On the basis of these ...[more]

PMID: 23214934

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Project description:The theory of electronic structure of many-electron systems, such as molecules, is extraordinarily complicated. A consideration of how electron density is distributed on average in the average field of the other electrons in the system, that is, mean field theory, is very instructive. However, quantitatively describing chemical bonds, reactions, and spectroscopy requires consideration of the way that electrons avoid each other while moving; this is called electron correlation (or in physics, the many-body problem for fermions). Although great progress has been made in theory, there is a need for incisive experimental tests for large molecular systems in the condensed phase. In this Account, we report a two-dimensional (2D) optical coherent spectroscopy that correlates the double-excited electronic states to constituent single-excited states. The technique, termed 2D double-quantum coherence spectroscopy (2D-DQCS), uses multiple, time-ordered ultrashort coherent optical pulses to create double- and single-quantum coherences over time intervals between the pulses. The resulting 2D electronic spectrum is a map of the energy correlation between the first excited state and two-photon allowed double-quantum states. The underlying principle of the experiment is that when the energy of the double-quantum state, viewed in simple models as a double HOMO-to-LUMO (highest occupied to lowest unoccupied molecular orbital) excitation, equals twice that of a single excitation, then no signal is radiated. However, electron-electron interactions, a combination of exchange interactions and electron correlation, in real systems generates a signal that reveals precisely how the energy of the double-quantum resonance differs from twice the single-quantum resonance. The energy shift measured in this experiment reveals how the second excitation is perturbed by both the presence of the first excitation and the way that the other electrons in the system have responded to the presence of that first excitation. We compare a series of organic dye molecules and find that the energy offset for adding a second electronic excitation to the system relative to the first excitation is on the order of tens of millielectronvolts; it also depends quite sensitively on molecular geometry. These results demonstrate the effectiveness of 2D-DQCS for elucidating quantitative information about electron-electron interactions, many-electron wave functions, and electron correlation in electronic excited states and excitons. Our work helps illuminate the implications of electron correlation on chemical systems. In a broad sense, we are trying to help address the fundamental question "How do we go beyond the orbital representation of electrons in the chemical sciences?"

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Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy.

Publications

Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy.

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