Probing drug-DNA interactions using super-resolution force spectroscopy

Abstract

Atomic magnetometry and ultrasound, as individual techniques, have been used extensively in various physical, chemical, and biomedical fields. Their combined application, however, has been rare. We report that super-resolution force spectroscopy, which is based on the integration of the two techniques, can find unique biophysical applications in studying drug-DNA interactions. The precisely controlled ultrasound generates acoustic radiation force on the biological systems labeled with magnetic microparticles. A decrease in the magnetic signal, measured by an automated atomic magnetometer, indicates that the acoustic radiation force equals the binding force of the biological system. With 0.5 pN force resolution, we were able to precisely resolve three small molecules binding with two DNA sequences and quantitatively reveal the effect of a single hydrogen bond. Our results indicate that the increases in DNA binding force caused by drug binding correlate with the enthalpy instead of free energy, thus providing an alternative physical parameter for optimizing chemotherapeutic drugs.

High‐Resolution DNA Dual‐Rulers Reveal a New Intermediate State in Ribosomal Frameshifting

“…The 12–15 bp duplexes were designed such that the dissociation forces stayed within the optimal detection range (ca. 10–70 pN) of SURFS [14] . By probing both ends of the mRNA, we obtained the precise frameshifting steps, which was a unique advantage of our method.…”

“…10-70 pN) of SURFS. [14] By probing both ends of the mRNA, we obtained the precise frameshifting steps, which was a unique advantage of our method. Figure 2b and c show the results of frameshifting without fusidic acid.…”

“…Meanwhile on the technical front, we invented super-resolution force spectroscopy (SURFS) by implementing acoustic radiation force, which was automatable and more precise than the centrifugal force used in FIRMS. [14] With 0.5 pN force resolution, we observed subnucleotide conformational difference between two different ribosome states within one translocation step. [15] Compared to other force-based techniques for ribosome research, mainly atomic force microscopy (AFM) and optical tweezers, [16,17] our approaches have the unique advantages of resolving different reading frames within the same sample, and probing both the moving edges of the ribosome.…”

“…With 2–4 pN force resolution, we were able to probe the mRNA positions with single‐nt resolution and observed a looped mRNA conformation trapped by antibiotics. Meanwhile on the technical front, we invented super‐resolution force spectroscopy (SURFS) by implementing acoustic radiation force, which was automatable and more precise than the centrifugal force used in FIRMS [14] . With 0.5 pN force resolution, we observed subnucleotide conformational difference between two different ribosome states within one translocation step [15] .…”

Advances in the Biological Application of Force-Induced Remnant Magnetization Spectroscopy

“…The force produced by precisely adjusted ultrasound radiation is capable of resolving the binding differences, such as antibody subclasses and single-base-pair DNA duplexes ( Figure 4 c) [ 34 ]. Subsequently, as the super-resolution force spectroscopy (SURFS), which is based on the integration of the atomic magnetometry and ultrasound techniques, has improved force resolution from 2 to 0.5 pN, the single hydrogen bond between drugs and DNA can be measured [ 35 ]. The increase in DNA binding force attributed to drug binding was observed to associate with the enthalpy change, thus providing an alternative physical parameter for optimizing chemotherapeutic drugs.…”