Can single molecule localization microscopy be used to map closely spaced RGD nanodomains?

PLoS One. 2017 Jul 19;12(7):e0180871. doi: 10.1371/journal.pone.0180871. eCollection 2017.

Abstract

Cells sense and respond to nanoscale variations in the distribution of ligands to adhesion receptors. This makes single molecule localization microscopy (SMLM) an attractive tool to map the distribution of ligands on nanopatterned surfaces. We explore the use of SMLM spatial cluster analysis to detect nanodomains of the cell adhesion-stimulating tripeptide arginine-glycine-aspartic acid (RGD). These domains were formed by the phase separation of block copolymers with controllable spacing on the scale of tens of nanometers. We first determined the topology of the block copolymer with atomic force microscopy (AFM) and then imaged the localization of individual RGD peptides with direct stochastic optical reconstruction microscopy (dSTORM). To compare the data, we analyzed the dSTORM data with DBSCAN (density-based spatial clustering application with noise). The ligand distribution and polymer topology are not necessary identical since peptides may attach to the polymer outside the nanodomains and/or coupling and detection of peptides within the nanodomains is incomplete. We therefore performed simulations to explore the extent to which nanodomains could be mapped with dSTORM. We found that successful detection of nanodomains by dSTORM was influenced by the inter-domain spacing and the localization precision of individual fluorophores, and less by non-specific absorption of ligands to the substratum. For example, under our imaging conditions, DBSCAN identification of nanodomains spaced further than 50 nm apart was largely independent of background localisations, while nanodomains spaced closer than 50 nm required a localization precision of ~11 nm to correctly estimate the modal nearest neighbor distance (NDD) between nanodomains. We therefore conclude that SMLM is a promising technique to directly map the distribution and nanoscale organization of ligands and would benefit from an improved localization precision.

MeSH terms

  • Cell Adhesion*
  • Cluster Analysis
  • Microscopy, Atomic Force / methods*
  • Oligopeptides / chemistry*
  • Single Molecule Imaging / methods*

Substances

  • Oligopeptides
  • arginyl-glycyl-aspartic acid

Grants and funding

This work was supported by the Australian Research Council; grant numbers LP140100967 (to KG and PRN) and DP130100269 (to KG). KG also acknowledges funding from the ARC Centre of Excellence in Advanced Molecular Imaging (CE140100011) and National Health and Medical Research Council of Australia (1059278, 1037320). JJB acknowledges funding from the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology (CE140100036) and the ARC Laureate Fellowship (FL150100060) program. The authors declare no competing interests.