a significant energetic barrier on the search, since the double-stranded DNA has to stretch by the same magnitude to check for homology. By formulating the DNA recognition process as a signal detection problem, it was shown that the experimentally observed RecA-induced DNA deformation and the binding energetics are fine-tuned to ensure optimal sequence detection. The amount of deformation is such that binding to homologous DNA sequences only slightly decreases, while binding to wrong sequences decreases significantly. This is exactly the conformational proofreading mechanism. Experimental evidence for conformational proofreading by homologous recombination The group of C. Dekker (Delft University) directly probed the interactions involved in homology search by combining magnetic and optical tweezers. They have found that homology search and recognition requires opening of the helix and can therefore be accelerated by unwinding the DNA. This is exactly the energy barrier predicted by the conformational proofreading model. The data indicate a physical picture for homology recognition in which the fidelity of the search process is governed by the distance between the DNA-binding sites. The authors conclude that their interpretation of the measurements "is akin to a conformational proofreading scheme ... where the dsDNA, and not the RecA filament, is the active, recognizing search entity. A large conformational mismatch exists between the target-bound and unbound states of the dsDNA. The target-bound state is accessed via energetically unfavorable intermediate states, as discussed above. The conformational mismatch improves the selectivity of the recognition reaction." In other words, they identified the energetic barrier and have shown that indeed the double-stranded DNA is the active participant, since it has to pass this barrier. Use by ribosome for tRNA decoding The ribosome is a complex molecular machine that, in order to synthesize proteins during the translation process, has to decode mRNAs by pairing their codons with matching tRNAs. Decoding is a major determinant of fitness and requires accurate and fast selection of correct tRNAs among many similar competitors. One must have in mind that most binding events are by non-matching (“non-cognate”) tRNAs and the ribosome needs to reject those as fast as possible in order to vacate the binding site. At the same time, the ribosome should keep the matching tRNAs bound long enough to allow the protein synthesis process ensue. Despite the importance of tRNA decoding, it was unclear until recently whether the modern ribosome, and in particular its large conformational changes during decoding, are the