Fluorescent polymerase enzyme substrates having protein shields

A labeled nucleotide analog comprising:

• (a) at least two avidin proteins having four subunits, each subunit comprising a biotin binding site;
• (b) one or more nucleotide components each bound to one or more of the avidin proteins through a biotin moiety, each nucleotide component comprising one or more nucleotide moieties;
• and
• (c) one or more dye components each bound to one or more of the avidin proteins, each dye component comprising one or more dye moieties.

A method for sequencing a nucleic acid template comprising:

• providing a polymerase enzyme complex comprising a polymerase enzyme, a template nucleic acid, and, optionally, a primer hybridized to the template nucleic acid, wherein the polymerase enzyme complex is immobilized on a surface;
• adding sequencing reagents in contact with the surface, the sequencing reagents comprising reagents for carrying out nucleic acid synthesis including two or more labeled nucleotide analogs of claim 1;
• and
• determining the sequential addition of nucleotides to a nucleic acid strand complementary to a strand of the template nucleic acid by observing the interaction of the labeled nucleotide analogs with the polymerase enzyme complex.

A system for sequencing nucleic acids comprising:

• a chip comprising a plurality of polymerase enzyme complexes bound thereto, each polymerase enzyme complex individually optically resolvable and comprising a polymerase enzyme, a template nucleic acid, and, optionally, a primer hybridized to the template nucleic acid;
• sequencing reagents in contact with the surface, the sequencing reagents comprising reagents for carrying out nucleic acid synthesis including two or more labeled nucleotide analogs of claim 1;
• an illumination system for illuminating the polymerase enzyme complexes;
• an optical detection system for detecting fluorescence from the labeled nucleotide analogs while they are interacting with the polymerase enzyme complexes;
• and
• a computer for analyzing the signals detected by the detection system to determine the sequential addition of nucleotides to a nucleic acid strand complementary to a strand of the template nucleic acid.