Differentiating amino acid residues and side chain orientations in peptides using scanning tunneling microscopy

J Am Chem Soc. 2013 Dec 11;135(49):18528-35. doi: 10.1021/ja408550a. Epub 2013 Dec 2.

Abstract

Single-molecule measurements of complex biological structures such as proteins are an attractive route for determining structures of the large number of important biomolecules that have proved refractory to analysis through standard techniques such as X-ray crystallography and nuclear magnetic resonance. We use a custom-built low-current scanning tunneling microscope to image peptide structures at the single-molecule scale in a model peptide that forms β sheets, a structural motif common in protein misfolding diseases. We successfully differentiate between histidine and alanine amino acid residues, and further differentiate side chain orientations in individual histidine residues, by correlating features in scanning tunneling microscope images with those in energy-optimized models. Beta sheets containing histidine residues are used as a model system due to the role histidine plays in transition metal binding associated with amyloid oligomerization in Alzheimer's and other diseases. Such measurements are a first step toward analyzing peptide and protein structures at the single-molecule level.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acids / chemistry*
  • Circular Dichroism
  • Crystallography, X-Ray
  • Microscopy, Atomic Force
  • Microscopy, Scanning Tunneling / methods*
  • Peptides / analysis*

Substances

  • Amino Acids
  • Peptides