The assembly of amyloid peptides into highly organized fibrils is one of the major characteristics of many degenerative diseases such as Alzheimer's disease and type II diabetes. Assembly structures of amyloid peptides at liquid-solid interface can be visualized by scanning tunneling microscopy (STM) with site-specific resolution. The STM analysis can provide valuable information on the folding mechanism of amyloid peptides based on the correlation of surface assembly structures and fibrillation behaviors. Cases on mutational analysis of amyloid peptides by STM are also reviewed which illustrate the capacities of STM studies on amyloid assemblies.

We illustrate in this work that pristine assemblies of amyloidal peptides can be obtained by perturbations of reduced scanning bias, and show a broad distribution in peptide length. In contrast, the chaperone-mediated peptide co-assembly presents ordered lamellar structures with a homogeneous distribution in length, which could be attributed to the core segment of the peptide. The efforts are beneficial for gaining insight into the aggregation propensity of peptides and inter-peptide interactions.

The peptide assembly structures of polyglutamine (PolyQ) have been studied by using scanning tunneling microscopy (STM) with high spatial resolution in ambient conditions. 4,4′-Bipyridyl (4Bpy) was introduced into the PolyQ₇ and PolyQ₈ peptide assemblies for labeling the C-termini of the peptides. The fine structures of the 4Bpy-PolyQ₇ and 4Bpy-PolyQ₈ co-assemblies are observed, and the statistics of the apparent peptide strand length reveal different length distributions for PolyQ₇ and PolyQ₈. One predominant apparent peptide strand length is observed for PolyQ₇ reflecting one predominant peptide conformation in assembly structures, while three major apparent strand lengths can be identified with PolyQ₈ reflecting three co-existing peptide conformations in peptide assemblies. Such drastic difference in assembling characteristics can be considered as a reflection of asymmetric adsorption effect of peptides relating to odd-even residue numbers of PolyQ₇ and PolyQ₈.

The unfolding process and self-assembly of a foldable oligomer (foldamer 1) at the liquid/graphite interface were investigated by scanning tunnelling microscopy. At the level of molecular conformation, we identified several molecular conformations (A_z, B, C, D, E) that represent intermediate states during unfolding, which may help to elucidate the unfolding process at the liquid/graphite interface. Adsorption at the interface traps the intermediate states of the unfolding process, and STM has proved to be a powerful technique for investigating folding and unfolding of a foldamer at the molecular level, which are not accessible by other methods. The STM observations also revealed that varying the solvent and/or concentration results in different self-assemblies of foldamer 1 as a result of variations in molecular conformations. The solvent and concentration effects were attributed to the changes in existing states (extended or folded) of foldamers in solution, which in turn affect the distribution of adsorbed molecular conformations at the interface. This mechanism is quite different from other systems in which solvent and concentration effects were also observed.

Scanning tunneling microscopy (STM) combined with density functional theory (DFT) calculations were applied in studying the anisotropic adsorption and condensation of tert-butylamine (t-BA) molecules in the vicinity of the steps on the Cu(111) surface. The preferential adsorption at the upper step edges and uneven distribution of t-BA in the vicinity of the steps illustrate the asymmetric electronic structure of the surface steps. Our observation demonstrates that the adsorption and diffusion of a polar molecule would be significantly mediated by steps on metal surfaces due to the molecule–step interaction and the intermolecular interactions.