Entropic Forces in Single-Biomolecule Mechanics Philip Nelson, University of Pennsylvania, DMR-0404674

Spare the Rod: 1. Intellectual merit

The DNA in our cells must not only store genetic information: It must constantly engage in mechanical rearrangements in the course being read, duplicated, and so on. Recent advances in the imaging and manipulation of single molecules seemed to show that a very simple mathematical model of DNA mechanics -- the “Elastic rod” model -- could describe its behavior very well. But the elastic rod picture seemed to rule out the very tightly-bent shapes that we know DNA frequently assumes in cells.

We imaged DNA using atomic force microscopy (above), obtaining unprecedented resolution (closeup below). We found that on the nanometer scale, relevant in cellular processes, DNA is much more flexible than had been predicted by the elastic rod model. [Images from PA Wiggins, T van der Heijden, F Moreno--Herrero, A Spakowitz, R Phillips, J Widom, C Dekker and PC Nelson, Nature Nanotechnology, in press.]

Our discovery of this unexpected, and biologically important, behavior of DNA relied on a tight interplay of theory and experiment, and illustrates the unity of scientific concepts. Ideas borrowed from renormalization-group theory (initially developed for the study of phase transitions) were crucial for initially formulating our hypothesis, and for the method we proposed to our experimental colleagues to test the hypothesis.

Besides being technically successful, our new model of DNA mechanics is mathematically very simple. This simplicity will make it a practical tool for explaining known DNA behavior, and for predicting new phenomena.

Entropic Forces in Single-Biomolecule Mechanics Philip Nelson, University of Pennsylvania, DMR-0404674

FURTHER REMARKS• Theorists view their job as seeking simplicity wherever it can legitimately be found, and in this we

succeeded. Generally, when we find a prevailing theory (elastic rod model) that breaks down when examined in a new regime (few-nanometer length scales), it’s necessary to replace it by a more complicated theory that embraces the old and the new results. In contrast, our new model is just as simple as elastic-rod, despite its larger domain of validity. Other, more complicated models exist, but we wanted one that real experimenters in the trenches could use for themselves.

• Theorists also seek to apply concepts discovered in one realm of science (here phase transitions) to other, seemingly distant, fields (here DNA in its fluctuating nanoworld). Our work illustrates the utility of such an approach.

• A vast literature, applying engineering-style beam-theory analysis to DNA, will now need to be reconsidered in the light of this discovery.

• AUTHOR CONTACT INFO• Paul Wiggins• * wiggins@wi.mit.edu• Whitehead Institute• * Cambridge• MA 02142• * United States of America• Work Telephone 1 617-324-2342

Entropic Forces in Single-Biomolecule Mechanics Philip Nelson, University of Pennsylvania, DMR-0404674

• Thijn van der Heijden• * heijden@mb.tn.tudelft.nl• Delft University• Kavli Institute of Nanoscience• Lorentzweg 1• * Delft 2628CJ• * Netherlands• Work phone +31 15 2782247 (6 hr later than EST)

• Fernando Moreno--Herrero• * moreno@mb.tn.tudelft.nl• Delft University• Kavli Institute of Nanoscience• Lorentzweg 1• * Delft 2628CJ• * Netherlands• Work phone +31 15 2782247 (6 hr later than EST)

Entropic Forces in Single-Biomolecule Mechanics Philip Nelson, University of Pennsylvania, DMR-0404674

• Rob Phillips•

* phillips@pboc.caltech.edu• Caltech• Eng Appl Sci• * Pasadena• CA• * United States of America• 91125• Work Phone (626) 395-3374, 818-919-2142• Jonathan Widom• * j-widom@northwestern.edu• Northwestern University• Department Biochem., Mol. Biol. & Cell Biol.• * Evanston• IL• * United States of America• 60208• Work phone (847) 467-1887; 224-522-1248

Entropic Forces in Single-Biomolecule Mechanics Philip Nelson, University of Pennsylvania, DMR-0404674

• Cees Dekker• * dekker@mb.tn.tudelft.nl• Delft University• Kavli Institute of Nanoscience• Lorentzweg 1• * Delft 2628CJ• * Netherlands• Phone +31 15 2786094(lab);+31 6 3036 2478(cell)

• Philip Nelson• * nelson@physics.upenn.edu• Univ Pennsylvania• Physics/Astronomy• * 209 S 33d St• * Philadelphia• PA• * United States of America• * 19146• Phone 215-898-7001• URL www.physics.upenn.edu/~pcn

A central issue for developmental cell biology is how genes get switched on and off. Biologists have long known that gene switching in some cells, such as bacteria, involves the formation of a loop of DNA. But again, there was a longstanding puzzle of how DNA could readily form loops as tight as the ones seen in living cells. Our work reconciles such observations with single-molecule studies that seemed to point to a very stiff DNA molecule. [Image from Hochschild, Curr Biol 12(2002).]

Entropic Forces in Single-Biomolecule Mechanics, Philip Nelson, University of Pennsylvania, DMR-0404674

DNA in our cells spend much of its time assembled into a small “bobbin” structure (the nucleosome). Our work helps explain the puzzle of how the supposedly DNA molecule -- till now regarded as essentially a very stiff elastic rod -- can easily adopt this tightly bent configuration. [Image from Richmond and Davey, Nature 423 (2003).]

Spare the Rod 2. Broader impact, education, manpower

Authors Wiggins and Spakowitz were grad students when this work was initiated. van der Heijden is completing his PhD; Moreno is a postdoc. Today Wiggins is a research associate at the Whitehead Institute, Spakowitz is on the engineering faculty at Stanford, and Moreno is heading for a research associate position in Spain.