Simulation of two-dimensional ultraviolet spectroscopy of amyloid fibrils

Abstract

Revealing the structure and aggregation mechanism of amyloid fibrils is essential for the treatment of over 20 diseases related to protein misfolding. Coherent two-dimensional (2D) infrared spectroscopy is a novel tool that provides a wealth of new insight into the structure and dynamics of biomolecular systems. Recently developed ultrafast laser sources are extending multidimensional spectroscopy into the ultraviolet (UV) region, and this opens up new opportunities for probing fibrils. In a simulation study, we show that 2DUV spectra of the backbone of a 32-residue β-amyloid (Aβ(9-40)) fibril associated with Alzheimer's disease and two intermediate prefibrillar structures carry characteristic signatures of fibril size and geometry that could be used to monitor its formation kinetics. The dependence of these signals on the fibril size and geometry is explored. We demonstrate that the dominant features of the β-amyloid fibril spectra are determined by intramolecular interactions within a single Aβ(9-40), and intermolecular interactions at the "external interface" have clear signatures in the fine details of these signals.

Figure 1

(A) Aβ_1–40 sequence and the structure of a single Aβ_9–40 peptide, with asymmetric “U” structure. N-terminal strand (red), C-terminal strand (blue), and turn region (green), respectively. (B) Model structure of amyloid fibril made of 12 Aβ_9–40 molecules. Red and blue indicate two parallel β-sheets.

Figure 2

The linear and 2D signals of native hen egg white lysozyme 2ZYP (left), β-sheet protofibril 1YJP (middle), and Aβ_9–40 amyloid fibril (right). From top to bottom: structures, and linear absorption, 2DUV xxxx, CD, and 2DUV xxxy spectra. CD and LA simulations are based on the electronic structure at 1000 snapshots along the MD trajectory. Red dotted and blue dashed lines in CD of lysozyme represent experimental results exp1 and exp2. Experimental CD and LA spectra of protofibril are given by red dotted lines. Red dotted and blue dashed lines in CD of amyloid fibril represent experimental results exp1 and exp2. 2DUV spectra are obtained by averaging over 500 MD snapshots. Red 2DUV signals are positive, and blue 2DUV signals are negative. L1-2-3, P1-2-3, and F1-2-3 in xxxy 2DUV spectra indicate the main diagonal signals, corresponding to the frequencies marked with dashed vertical line in CD and LA spectra. The 2DUV spectra normalization (R) factors from left to right: for xxxx − 0.42, 0.38, 0.20; for xxxy − 0.10, 0.44, 0.09.

Figure 3

Transition populations of native lysozyme 2ZYP, protofibril 1YJP, Aβ_9–40 fibril averaged over 500 MD snapshots. L1-2-3, P1-2-3, and F1-2-3 correspond to the xxxy 2DUV peaks marked in Fig. Figure 2.

Figure 4

Variation of CD, LA and 2DUV spectra with the number of structural elements in Aβ_9–40 amyloid fibrils. From top to bottom: structures, and absorption, 2DUV xxxx, CD, and 2DUV xxxy spectra. Linear and 2D signals are based on 1000 and 500 MD snapshots, respectively. Red 2DUV signals are positive, and blue 2DUV signals are negative. The 2DUV spectra normalization (R) factors from left to right: for xxxx − 0.38, 0.41, 0.36, 0.33; for xxxy − 0.42, 0.24, 0.18, 0.11.

Figure 5

Structures, CD, LA and 2DUV spectra of an Aβ_9–40 molecule and its different fragments. From top to bottom: structures, and absorption, 2DUV xxxx, CD, and 2DUV xxxy spectra. Linear and 2D signals are based on 1000 and 500 MD snapshots, respectively. Red 2DUV signals are positive, and blue 2DUV signals are negative. The 2DUV spectra normalization (R) factors from left to right: for xxxx − 0.38, 0.82, 0.40, 0.43, 0.56; for xxxy − 0.42, 0.62, 0.42, 0.51, 1.11.