Methods and apparatus that increase sequencing-by-binding efficiency

A method of nucleic acid detection, comprising.

• (a) sequentially contacting a primed template nucleic acid with first and second mixtures under ternary complex stabilizing conditions, wherein each of the mixtures comprises a polymerase and nucleotide cognates for four different base types in the primed template nucleic acid, wherein each of the mixtures comprises a first subset of two exogenously labeled nucleotides that produce detectable signals and a second subset of two nucleotides that do not produce the detectable signals, wherein the mixtures differ by at least one type of nucleotide cognate;
• (b) examining the first and second mixtures separately to detect ternary complexes that produce the signals;
• and
• (c) identifying the next correct nucleotide for the primed template nucleic acid molecule, wherein the next correct nucleotide is identified as a cognate of a first base type if ternary complex is detected in the first mixture but not the second mixture, and wherein the next correct nucleotide is identified as a cognate of a second base type if ternary complex is detected in the second mixture but not the first mixture.