לוח שנה משולב

In contrast to proteins recognizing small-molecule ligands, DNA-dependent enzymes cannot rely solely on interactions in the substrate-binding centre to achieve their exquisite specificity. It is widely believed that substrate recognition by such enzymes involves a series of conformational changes in the enzyme-DNA complex with sequential gates favoring cognate DNA and rejecting nonsubstrates. However, direct evidence for such mechanism is limited to a few systems. We used molecular dynamics simulations to explore the dynamic recognition of oxidative DNA damage by glycosylase enzymes. The resulting energy profiles, supported by biochemical analysis of site-directed mutants disturbing the interactions along the proposed path, show that the glycosylases selectively facilitate recognition by stabilizing several intermediate states, helping the rapidly sliding enzyme avoid full extrusion of every encountered base for interrogation. Lesion recognition through multiple gating intermediates may be a common theme in DNA repair enzymes; we show that human and bacterial enzymes share a common recognition mechansim despite lack of sequence or structural similarity of their glycosylases.

Thermodynamics provides a robust conceptual framework and set of laws that govern the exchange of energy and matter. Although these laws were originally articulated for macroscopic objects, nanoscale systems often exhibit “thermodynamic-like” behavior – biomolecular motors convert chemical fuel into mechanical work, and individual polymer molecules exhibit hysteresis and dissipation when stretched and contracted. To what extent can the laws of thermodynamics be “scaled down” to apply to individual microscopic systems, and what new features emerge at the nanoscale? I will review recent progress toward answering these questions.
The second law of thermodynamics is traditionally stated in terms of inequalities. For microscopic systems these inequalities can be replaced by stronger equalities, known as fluctuation relations, which relate equilib-rium properties to far-from-equilibrium fluctuations. The discovery and experimental validation of these rela-tions has stimulated interest in the feedback control of small systems, the closely related Maxwell demon par-adox, and the interpretation of the thermodynamic arrow of time. These developments have led to new tools for the analysis of non-equilibrium experiments and simulations, and they have refined our understanding of irreversibility and the second law.
I will also discuss challenges and open questions, including how to extend fluctuation relations to quantum systems, and how to formulate the first law of thermodynamics properly, when the interaction energy be-tween the system and its thermal surroundings cannot be neglected.