Predicting the Torsional Dynamics of DNA

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

While the double-helical form of DNA is well-known, fundamental questions remain concerning how its biological functions are influenced by its structure. By structure, we refer to the time-dependent shape and stress of this amazingly long and flexible biopolymer. Understanding DNA structure-function relations rests on quantifying the torsional dynamics of the molecule as torsion is implicated in all major DNA functions including compaction, transcription, replication, gene regulation, gene repair, etc. Our project addresses this need by proposing new experimental and theoretical methods for revealing the torsional dynamics of DNA at the single molecule level. In particular, we introduce a novel detection method employing a magnetic, optically modulated bead (mag-MOON) to measure the dynamic twisting of DNA molecules tethered to these beads. Simultaneously, we extend a computational rod model describing the coupled nonlinear dynamics of the tethered DNA-bead system that enables model validation from the companion single-molecule DNA experiments. Our research on DNA torsional dynamics has broader implications for the medical and physical sciences. Consider that specific anti-cancer drugs (e.g., Topotecan) target proteins (e.g., Topoisomerase I) that relieve the build up of torsional stress and supercoils during DNA replication. By essentially blocking the torsional relaxation of DNA, these drugs inhibit the division (hence propagation) of diseased cells. Increasing the efficacy of these chemotherapeutic drugs rests on first understanding their action on torsionally-stressed DNA. We assert that such understanding may ultimately grow from fundamental knowledge of the torsional mechanics of DNA as achieved through systematic experimental/theoretical efforts. Our experiments also introduce a novel molecular ?twist detector? in the form of a mag-MOON bead. While clearly advantageous for single-molecule DNA studies, this novel technique may translate to uses in other biomolecular systems or nano-scale devices where molecular rotation plays a major role (e.g., molecular motor proteins, molecular wheels, rotaxanes, bacterial flagella, ATP synthase, RecA).