Single-molecule mechanics: New insights from the escape-over-a-barrier problem

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The early description of the living cell as a reaction vessel of molecules undergoing random collisions has evolved to a much more interesting picture of a small chemical factory of complex and dynamic molecular structures that carry out specialized functions in a highly-coordinated fashion. Traditional solution biochemistry has had extraordinary success in elucidating molecular structures of the cellular components. The task of capturing the dynamics and the distribution of states of these structures, however, seemed nearly impossible because the activities of the molecules in the solution are asynchronous as the result of their interactions with the surroundings. This situation has changed with the development of single-molecule biophysical methods (1, 2) that permit measurements of the response of macromolecules or individual molecular bonds to external load with the spectacular resolution of subnanometer distances and picoNewton forces, revealing details that are typically lost to ensemble averaging when studied by solution methods. Unprecedented information about the mechanisms that drive biological processes becomes encoded in the resulting wealth of unaveraged data. Recall, however, that these systems are of microscopic dimensions, which puts thermal fluctuations on equal footing with the external deterministic forces. This circumstance, along with the far from equilibrium conditions, makes a quantitative description of the molecular bond properties that can account for observed data a challenging task. The article by Freund in this issue of PNAS (3) offers a theoretical framework that does just that. A novel and concise derivation takes the reader from a very fundamental starting point to a set of analytical results that provide intriguing insights into the response of a molecular bond to an imposed mechanical load.