Conformational proofreading
Encyclopedia
Conformational proofreading is a general mechanism of molecular recognition
systems, in which introducing a structural mismatch between a molecular recognizer and its target enhances the recognition specificity and quality.
mechanism, are advantageous for enhancing the specificity of recognition .
facilitates the exchange of genetic material between homologous DNA molecules. This crucial process requires detecting a specific homologous DNA sequence within a huge variety of heterologous sequences. The detection is mediated by RecA
in E. coli, or members of its superfamily in other organisms. RecA first polymerizes along a stretch of single-stranded DNA, and then this protein-DNA filament searches for homology along double-stranded DNA. In the RecA-DNA filament, the distance between bases increases significantly with respect to the bare 3.4 Å in the double-strand (by 50% on average ).
This sets 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.
schema, a time delay (equivalently, an irreversible intermediate stage) is introduced during the formation of the correct or incorrect complexes. This time delay reduces the production rates of both complexes but enhances the fidelity beyond the equilibrium limit. The irreversibility of the scheme requires an energy source. The time delay in kinetic proofreading is analogous to the spatial difference in conformational proofreading. However, the conformational proofreading is an equilibrium scheme that does not consume energy.
Molecular recognition
The term molecular recognition refers to the specific interaction between two or more molecules through noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, electrostatic and/or electromagnetic effects...
systems, in which introducing a structural mismatch between a molecular recognizer and its target enhances the recognition specificity and quality.
Balancing correct and incorrect binding
Molecular recognition takes place in a noisy, crowded biological environment and the recognizer often has to cope with the task of selecting its target among a variety of similar competitors. For example, the ribosome has to select the correct tRNA that matches the mRNA codon among many structurally similar tRNAs. If the recognizer and its correct target match perfectly like a lock and a key, then the binding probability will be high since no deformation is required upon binding. At the same time, the recognizer might also bind to a competitor with a similar structure with high probability. Introducing a structural mismatch between the recognizer and reduces the binding probability to the correct target but reduces even more the binding probability to a similar wrong target and thus improves the specificity. Yet, introducing too much deformation drastically reduce binding probability to the correct target. Therefore, the optimal balance between maximizing the correct binding probability and minimizing the incorrect binding probability is achieved when the recognizer is slightly off target. This suggests that conformational changes during molecular recognition processes, such as the induced fitEnzyme catalysis
Enzyme catalysis is the catalysis of chemical reactions by specialized proteins known as enzymes. Catalysis of biochemical reactions in the cell is vital due to the very low reaction rates of the uncatalysed reactions....
mechanism, are advantageous for enhancing the specificity of recognition .
Conformational Proofreading in Homologous Recombination
The mechanism of conformational proofreading is utilized in the system of homologous recombination to discern between similar DNA sequences . Homologous recombinationHomologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
facilitates the exchange of genetic material between homologous DNA molecules. This crucial process requires detecting a specific homologous DNA sequence within a huge variety of heterologous sequences. The detection is mediated by RecA
RecA
RecA is a 38 kilodalton Escherichia coli protein essential for the repair and maintenance of DNA. RecA has a structural and functional homolog in every species in which it has been seriously sought and serves as an archetype for this class of homologous DNA repair proteins...
in E. coli, or members of its superfamily in other organisms. RecA first polymerizes along a stretch of single-stranded DNA, and then this protein-DNA filament searches for homology along double-stranded DNA. In the RecA-DNA filament, the distance between bases increases significantly with respect to the bare 3.4 Å in the double-strand (by 50% on average ).
This sets 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.
Relation to kinetic proofreading
In the kinetic proofreadingKinetic proofreading
Kinetic proofreading is a mechanism for error correction in biological processes, proposed independently by John Hopfield and Jacques Ninio...
schema, a time delay (equivalently, an irreversible intermediate stage) is introduced during the formation of the correct or incorrect complexes. This time delay reduces the production rates of both complexes but enhances the fidelity beyond the equilibrium limit. The irreversibility of the scheme requires an energy source. The time delay in kinetic proofreading is analogous to the spatial difference in conformational proofreading. However, the conformational proofreading is an equilibrium scheme that does not consume energy.