Measurements of molecular size and shape on a chip

Abstract

Size and shape are critical discriminators between molecular species and states. We describe a micro-chip based high-throughput imaging approach offering rapid and precise determination of molecular properties under native solution conditions. Our method detects differences in molecular weight across at least three orders of magnitude, and down to two carbon atoms in small molecules. We quantify the strength of molecular interactions over six orders of magnitude in affinity constant, and track reactions in real-time. Highly parallel measurements on individual molecules serve to characterize sample-state heterogeneity at the highest resolution, offering predictive input to model three-dimensional structure. We further leverage the method's structural sensitivity for diagnostics, exploiting ligand-induced conformational changes in the insulin receptor to sense insulin concentration in serum at the sub-nanoliter and sub-zeptomole scale.