Devices and methods for determining molecular structure

Abstract

A method of determining the structure of a molecule can include labeling a first location on the molecule with a first DNA strand, and measuring a force-time waveform using the twisting of a T-shaped atomic force microscope cantilever scanning across the molecule. The cantilever can include a DNA probe having a first region that is complimentary to the first DNA strand.

1 ) A method of determining the structure of a molecule, comprising:
 labeling a first location on the molecule with a first DNA strand;   measuring a force-time waveform using the twisting of a T-shaped atomic force microscope cantilever scanning across the molecule, wherein the cantilever includes a DNA probe having a first region that is complimentary to the first DNA strand.   
     
     
         2 ) The method of  claim 1 , wherein the molecule is a protein. 
     
     
         3 ) The method of  claim 1 , wherein the molecule is one of a protein complexed with DNA, a protein complexed with RNA, a protein complexed with both DNA and RNA, a sugar or a lipid. 
     
     
         4 ) The method of  claim 1 , wherein labeling a first location further comprises replacing a native amino acid located at the first location with a first replacement amino acid and binding the first DNA strand to the first replacement amino acid. 
     
     
         5 ) The method of  claim 1 , wherein labeling the first location further comprises binding a biotin molecule to the first location, and binding the biotin molecule to the first DNA strand. 
     
     
         6 ) The method of  claim 1 , further comprising labeling a second location on the molecule with a second DNA strand; and wherein the DNA probe includes a second region that is complimentary to the second DNA strand. 
     
     
         7 ) The method of  claim 6 , wherein labeling a second location further comprises replacing a native amino acid located at the second location with a second replacement amino acid and binding the second DNA strand to the second replacement amino acid. 
     
     
         8 ) The method of  claim 6 , wherein labeling the second location further comprises binding a biotin molecule to the second location, and binding the biotin molecule to the second DNA strand. 
     
     
         9 ) The method of  claim 1 , further comprising labeling a plurality of locations on the molecule with a plurality of DNA strands, and wherein the DNA probe has a complimentary region for each of the DNA strands. 
     
     
         10 ) The method of  claim 9 , further comprising measuring pairwise distances between each of the DNA strands. 
     
     
         11 ) The method of  claim 10 , further comprising determining a three-dimensional structure based at least in part on the pairwise distances. 
     
     
         12 ) The method of  claim 1 , wherein the first DNA strand is between 2 and 30-base-long single-stranded DNA. 
     
     
         13 ) The method of  claim 1 , wherein scanning comprises a fluid tapping mode. 
     
     
         14 ) An atomic force microscope for determining the structure of a molecule having a first location labeled with a first DNA strand, comprising:
 a cantilever having
 a body having T-shaped geometry including a base, a first end and a second end; 
 a tip, disposed at one of the first and second end; and 
 a DNA probe, coupled to the tip, and having a first region that is complimentary to the first DNA strand. 
   
     
     
         15 ) The device of  claim 14 , wherein the body comprises silicon nitride. 
     
     
         16 ) The device of  claim 14 , wherein the tip comprises silicon. 
     
     
         17 ) The device of  claim 14 , wherein the cantilever has a resonance frequency between 4 and 1.20 MHz. 
     
     
         18 ) The device of  claim 14 , wherein the cantilever has a spring constant of the vertical deflections between 35 pN/nm and 200 pN/nm. 
     
     
         19 ) The device of  claim 14 , wherein the cantilever has a spring constant of torsional modes between 200 pN/nm and 400 pN/nm. 
     
     
         20 ) The device of  claim 14 , wherein the DNA probe includes a second region that is complimentary to a second DNA strand coupled to a second location on the molecule.