Molecular dynamics simulation suggests possible interaction patterns at early steps of beta2-microglobulin aggregation

Abstract

Early events in aggregation of proteins are not easily accessible by experiments. In this work, we perform a 5-ns molecular dynamics simulation of an ensemble of 27 copies of beta(2)-microglobulin in explicit solvent. During the simulation, the formation of intermolecular contacts is observed. The simulation highlights the importance of apical residues and, in particular, of those at the N-terminus end of the molecule. The most frequently found pattern of interaction involves a head-to-head contact arrangement of molecules. Hydrophobic contacts appear to be important for the establishment of long-lived (on the simulation timescale) contacts. Although early events on the pathway to aggregation and fibril formation are not directly related to the end-state of the process, which is reached on a much longer timescale, simulation results are consistent with experimental data and in general with a parallel arrangement of intermolecular beta-strand pairs.

FIGURE 1

Root mean-square deviation of C_αs from the starting crystal structure (PDB code 3HLA, chain B) versus simulation time. The average and error bars are computed over the ensemble of 27 molecules.

FIGURE 2

RMSD versus residue at the end of the simulation. The average deviation from the starting structure is shown by a thick line. The average deviation upon pairwise superposition of all 27 structures onto each other is shown by a thin line.

FIGURE 3

Number of contacts versus residue. For definitions of contact and molecular ensemble, see text.

FIGURE 4

Apical location of the most important contacting residues. The side chain of residues 1, 3, 16, 17, 18, 31, 34, 48, 50, 56, 58, 59, 60, 74, 75, 91, 97, 98, 99 is shown. The N-terminal (head) apex of the molecule is displayed at the top of the figure. The C-terminal (tail) apex is displayed at the bottom of the figure.

FIGURE 5

All the selected pairs of molecules are displayed in such a way that one of the two molecules is superimposed on the starting structure. The head residues are colored in red, the tail residues are colored in green (upper left). The most populated cluster displays a head-to-head arrangement (upper right). The second- and third- most populated clusters display a tail-to-tail arrangement (lower left). The fourth-most populated cluster displays an antiparallel arrangement (lower right).

FIGURE 6

The electrostatic potential at the surface of β₂-microglobulin (upper) and isopotential surfaces (lower). Blue is saturated at 1.0 kcal mol⁻¹ q⁻¹ and red at −1.0 kcal mol⁻¹ q⁻¹. The blue isopotential surface refers to 0.5 kcal mol⁻¹ q⁻¹ and red to −0.5 kcal mol⁻¹ q⁻¹. The pictures at right refer to the molecule rotated by 180° about the vertical axis.

FIGURE 7

Snapshots taken at 1-ns intervals of four selected β₂-microglobulin molecules.